The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%; and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently–6% of IDDM and 1% of NIDDM patients. Overall, two thirds of diabetic patients have objective evidence for some variety of neuropathy, but only about 20% have symptoms, and only 6% of IDDM and only 1% of NIDDM patients have sufficiently severe polyneuropathy to be graded stage 2b, and none were graded stage 3. Approximately one quarter of patients had subclinical carpal tunnel syndrome, but only 7.7% had symptomatic carpal tunnel syndrome. Thus, diabetic peripheral neuropathy is frequent but less severe than generally thought. As generally believed, however, neuropathy, retinopathy, and nephropathy are significantly associated.

Metabolism of methanol, methyl ethers, esters and amides give rise to formic acid. This acid is an inhibitor of the mitochondrial cytochrome oxidase causing histotoxic hypoxia. Formic acid is a weaker inhibitor than cyanide and hydrosulphide anions. The body burden of formate in methanol poisoning is high enough to cause acidosis, and other clinical symptoms. Part of the protons can be attributed to formic acid whereas the most significant acid load results from the hypoxic metabolism. The acidosis causes e.g. dilatation of cerebral vessels, facilitation of the entry of calcium ions into cells, loss of lysosomal latency and deranged production of ATP. The latter effect seems to impede parathormone-dependent calcium reabsorption in the kidney tubules. Besides, urinary acidification is affected by formic acid. Its excretion causes continuous recycling of the acid by the tubular cell Cl-/formate exchanger. This sequence of events may partially explain an accumulation of formate in urine. Occupational exposure to vapours of methanol and formic acid can be quantitatively monitored by urinary formic acid determinations. Formic acid toxicity may prove a suitable model for agents causing histotoxic hypoxia.

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BACKGROUND: Mortality is very high in lactic acidosis, and there is no satisfactory treatment other than treatment of the underlying cause. Uncontrolled studies have suggested that dichloroacetate, which stimulates the oxidation of lactate to acetyl-coenzyme A and carbon dioxide, might reduce morbidity and improve survival among patients with this condition. METHODS: We conducted a placebo-controlled, randomized trial of intravenous sodium dichloroacetate therapy in 252 patients with lactic acidosis; 126 were assigned to receive dichloroacetate and 126 to receive placebo. The entry criteria included an arterial-blood lactate concentration of > or = 5.0 mmol per liter and either an arterial-blood pH of < or = 7.35 or a base deficit of > or = 6 mmol per liter. The mean (+/- SD) arterial-blood lactate concentrations before treatment were 11.6 +/- 7.0 mmol per liter in the dichloroacetate-treated patients and 10.4 +/- 5.5 mmol per liter in the placebo group, and the mean initial arterial-blood pH values were 7.24 +/- 0.12 and 7.24 +/- 0.13, respectively. Eighty-six percent of the patients required mechanical ventilation, and 74 percent required pressor agents, inotropic drugs, or both because of hypotension. RESULTS: The arterial-blood lactate concentration decreased 20 percent or more in 83 (66 percent) of the 126 patients who received dichloroacetate and 45 (36 percent) of the 126 patients who received placebo (P = 0.001). The arterial-blood pH also increased more in the dichloroacetate-treated patients (P = 0.005). The absolute magnitude of the differences was small, however, and they were not associated with improvement in hemodynamics or survival. Only 12 percent of the dichloroacetate-treated patients and 17 percent of the placebo patients survived to be discharged from the hospital. CONCLUSIONS: Dichloroacetate treatment of patients with severe lactic acidosis results in statistically significant but clinically unimportant changes in arterial-blood lactate concentrations and pH and fails to alter either hemodynamics or survival.

We administered dichloroacetate, which prevents or reverses hyperlactatemia in animals and lowers plasma lactate levels in human beings, to 13 patients with lactic acidosis of various causes. All had hypotension, and their acidemia had resisted treatment with sodium bicarbonate. The metabolic effects of dichloroacetate were evaluated in 11 patients. In seven dichloroacetate significantly reduced the level of arterial blood lactate (P less than 0.005) from the base-line value and raised the levels of arterial blood bicarbonate (P less than 0.02) and arterial pH (P less than 0.005). In six of these seven, the acidemia resolved completely with therapy. In 10 of the 13 patients systolic blood pressure increased by 10 to 40 mm Hg, and 4 patients had a 21 per cent increase in cardiac output (P less than 0.02). Despite improvement in their lactic acidemia, all patients but one died of their underlying disease. No serious drug-related toxicity occurred. We conclude that dichloroacetate is a safe and effective adjunct in the treatment of patients with lactic acidosis, although the ultimate prognosis may depend on the underlying disease.

OBJECTIVE: To evaluate the role of chronic cerebral lactic acidosis in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). METHODS: The authors studied 91 individuals from 34 families with MELAS and the A3243G point mutation and 15 individuals from two families with myoclonus epilepsy and ragged red fibers (MERRF) and the A8344G mutation. Subjects were divided into four groups. Paternal relatives were studied as controls (Group 1). The maternally related subjects were divided clinically into three groups: asymptomatic (no clinical evidence of neurologic disease) (Group 2), oligosymptomatic (neurologic symptoms but without the full clinical picture of MELAS or MERRF) (Group 3), and symptomatic (fulfilling MELAS or MERRF criteria) (Group 4). The authors performed a standardized neurologic examination, neuropsychological testing, MRS, and leukocyte DNA analysis in all subjects. RESULTS: The symptomatic and oligosymptomatic MELAS subjects had significantly higher ventricular lactate than the other groups. There was a significant correlation between degree of neuropsychological and neurologic impairment and cerebral lactic acidosis as estimated by ventricular MRS lactate levels. CONCLUSIONS: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, are associated with more severe neurologic impairment.

We performed a short-term, double-blind, placebo-controlled, crossover trial of sodium dichloroacetate (DCA) therapy in 11 patients affected by various primary mitochondrial disorders. Independent measures of oxidative metabolism (venous blood metabolites, exercise testing, phosphorus magnetic resonance [MR] spectroscopy of muscle, and proton MR spectroscopy of brain) were used in order to monitor metabolic responses to the drug. One week of DCA treatment produced significant decreases (p < 0.05) in blood lactate, pyruvate, and alanine at rest and after bicycle exercise. Proton MR spectra collected from a supraventricular volume of interest in brain of seven of 11 patients also showed significant changes. Brain lactate/creatine ratio decreased by 42% during DCA treatment (p < 0.05). Brain choline/creatine ratio (which is low in patients with myelinopathies) increased by 18% (p < 0.01) after therapy. N-Acetylaspartate/creatine ratio (an index of neuronal damage or loss) increased by 8% after treatment (p < 0.05). Proton MR spectra collected in two of 11 patients from a volume of interest including the basal ganglia showed similar results (decrease of 36.6% in lactate/creatine; increases of 16% in choline/creatine and 4.5% in N-acetylaspartate/creatine). Phosphorus MR spectroscopy of muscle and self-assessed clinical disability were unchanged. Our study indicates that short-term DCA treatment not only lowers blood lactate but also improves indices of both brain oxidative metabolism and neuronal and glial density or function.

PURPOSE OF REVIEW: Peripheral neuropathy is a common neurotoxic effect of medications. When medications are used to treat life-threatening illnesses, balancing the toxic effects of peripheral neuropathy with the therapeutic benefits of the drug can be difficult. This article examines recent research into the cellular mechanisms associated with neuropathy after treatment with medications to treat cancer, and HIV, and to prevent transplant rejection. RECENT FINDINGS: Cisplatin and suramin induce a length, dose, and time-dependent axonal sensorimotor polyneuropathy. Cisplatin and suramin both result in apoptosis in dorsal root ganglion neurons that may partially explain the neuropathy that develops with treatment. In contrast, nerve growth factor prevents initiation of the programmed cell death associated with cisplatin neurotoxicity. Suramin causes accumulation of lamellar inclusion bodies in dorsal root ganglion neurons related to dose of administration and severity of the neuropathy. Nucleoside reverse transcriptase inhibitors affect mitochondrial function and lead to depletion of the nerve’s mitochondrial DNA and inhibition of DNA polymerase. These effects on the mitochondrion may be related to the polyneuropathy that develops in these patients. In contrast to the axonal neuropathies, tacrolimus and rarely suramin can result in a demyelinating neuropathy that may mimic Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. Many of these neuropathies can be reversed by early recognition of the symptoms or by using sensitive electrophysiological testing. In certain instances, specific therapies may ameliorate the neuropathy. Glutamine may reduce paclitaxel-induced toxicity, while some patients with tacrolimus or suramin-induced demyelinating neuropathy may respond to intravenous immunoglobulin or plasmapheresis. SUMMARY: Improved understanding of neurotoxic mechanisms in the peripheral nervous system associated with chemotherapeutic and anti-HIV medications, coupled with early improved diagnosis, promises to help limit neurotoxicity associated with these medications.

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The genes encoding succinate dehydrogenase (SDH) subunits B, C and D, act as tumour suppressors in neuro-endocrine tissues. Tumour formation has been associated with succinate accumulation. In paraganglioma cells, two forms of SDHA (type I, II) were found which might preclude significant succinate accumulation in the case of a mutation in either form. In fibroblasts only SDHA type I is found. In these cells, SDHA type I mutation leads to SDH deficiency, succinate accumulation and hypoxia-inducible factor 1alpha(HIF1alpha) nuclear translocation. HIF1alpha nuclear translocation was not observed in ATPase-deficient fibroblasts with increased superoxide production and was found to be independent of cellular iron availability in SDHA-mutant cells. This suggests that neither superoxides nor iron were causative of HIF1alpha nuclear translocation. Conversely, alpha-ketoglutarate (alpha-KG) inhibits this nuclear translocation. Therefore, the pseudo-hypoxia pathway in SDH-deficient cells depends on the HIF1alphaprolyl hydroxylase product/substrate (succinate/alpha-KG) equilibrium. In SDH deficiency, organic acids thus appear instrumental in the HIF1alpha-dependent cascade suggesting a direct link between SDH and tumourigenesis.

Autopsy examination confirmed the diagnosis of subacute necrotizing encephalomyelopathy (SNE) in a 7-month-old male infant who underwent several metabolic studies before death. Intermittent lactic acidemia and fumaric aciduria, an extreme hyperglycemic response to an intravenous bolus of alanine, and an elevated total body flux rate of glucose (58.4 mumoles . kg-1 . min-1) suggested a disturbance in the oxidative decarboxylation of pyruvate. Enzymological studies of postmortem samples revealed low nonactivated pyruvate dehydrogenase activity in liver (19.4%) and brain (53.8%). The lowest brain pyruvate dehydrogenase activities were noted in the midbrain and pontine regions. Supramaximal activation of the hepatic pyruvate dehydrogenase complex (135% of control values) occurred in vitro. Spontaneous reactivation following in vitro inactivation of the complex with adenosine triphosphate was significantly less (p less than 0.02) in the patient’s samples compared to controls. The biochemical defect was not apparent in fibroblasts. These enzymological observations point to an in vivo defect in the activation mechanism of the pyruvate dehydrogenase complex as the biochemical disturbance in SNE. The findings suggest that dichloroacetate may be beneficial in treating SNE.

To evaluate the role of chronic cerebral lactic acidosis in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).The authors studied 91 individuals from 34 families with MELAS and the A3243G point mutation and 15 individuals from two families with myoclonus epilepsy and ragged red fibers (MERRF) and the A8344G mutation. Subjects were divided into four groups. Paternal relatives were studied as controls (Group 1). The maternally related subjects were divided clinically into three groups: asymptomatic (no clinical evidence of neurologic disease) (Group 2), oligosymptomatic (neurologic symptoms but without the full clinical picture of MELAS or MERRF) (Group 3), and symptomatic (fulfilling MELAS or MERRF criteria) (Group 4). The authors performed a standardized neurologic examination, neuropsychological testing, MRS, and leukocyte DNA analysis in all subjects.The symptomatic and oligosymptomatic MELAS subjects had significantly higher ventricular lactate than the other groups. There was a significant correlation between degree of neuropsychological and neurologic impairment and cerebral lactic acidosis as estimated by ventricular MRS lactate levels.High levels of ventricular lactate, the brain spectroscopic signature of MELAS, are associated with more severe neurologic impairment.

Aging is accompanied by a progressive decline in mitochondrial quality, bioenergetic flexibility, and stress resilience. Aging mitochondria are increasingly recognized as active inflammatory signaling platforms rather than passive targets of cellular damage. Excess mtROS, leaked mtDNA, defective mitophagy, altered NAD+ metabolism, and impaired pyruvate oxidation together create a cellular environment that favors persistent inflammatory activation. These signals engage NF-κB, NLRP3 inflammasome, cGAS–STING, and SASP pathways, allowing mitochondrial stress to spread from organelle dysfunction to tissue-level inflammation. Within this framework, pyruvate dehydrogenase kinase 4 (PDK4) is of particular interest because it directly controls mitochondrial pyruvate entry through inhibition of the pyruvate dehydrogenase complex. By phosphorylating and inhibiting the pyruvate dehydrogenase complex, PDK4 limits mitochondrial pyruvate oxidation and favors lactate accumulation, fatty acid utilization, and redox-inflammatory signaling. Recent work in senescent cells links PDK4-dependent lactate accumulation to NOX1-derived ROS and SASP activity, suggesting a direct route by which altered fuel handling may reinforce inflammation. Here, we review mitochondrial dysfunction as the organizing principle of age-associated meta-inflammation, discuss PDK4 as a central metabolic checkpoint, examine tissue-specific consequences in muscle, adipose tissue, brain, and kidney, and evaluate therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan.

Solid tumours resist adoptive cell therapies through lactate driven immunosuppression, which depletes intracellular nicotinamide adenine dinucleotide, suppresses interferon gamma production in T cells, and reprogrammes macrophages. Here we show that a dual compartment lipid carrier system hijacks exocytosis for spatiotemporal metabolic reprogramming. Lipid nanoparticles deliver nicotinamide mononucleotide to restore intracellular nicotinamide adenine dinucleotide, while endoplasmic reticulum targeted carriers exploit the endoplasmic reticulum to Golgi pathway to achieve trafficking directed exocytic dichloroacetate export, enabling precise lactate depletion without systemic toxicity. This integrated approach rewires the metabolic landscape, extends natural killer cell persistence and reactivates cytolytic function. Endoplasmic reticulum engineered natural killer cells achieve potent tumour suppression through spatiotemporal metabolic reprogramming, a platform strategy that also extends to conventional T cell and macrophage therapies for enhanced therapeutic efficacy across adoptive cell systems. Our work establishes exocytosis co option as a strategy to empower cellular therapies and improve antitumour efficacy against lactate rich solid cancers.

Myocardial infarction, characterized by irreversible cardiomyocyte loss, progressive cardiac fibrosis and subsequent deteriorated heart function, constitute an intractable global health burden. Promoting endogenous cardiomyocyte proliferation to achieve functional cardiac regeneration represents an available foreground for combatting heart failure. Based on extensive preclinical evidence, researchers have characterized the cellular and molecular mechanisms governing cardiomyocyte proliferation and elucidated the modulatory influence of the metabolic factors and extracellular matrix. Insights from various studies have facilitated the development of regenerative approaches that reprogramming terminally differentiated cardiomyocytes toward a more metabolic plastic and fetal-like state, thereby enhancing the proliferative and reparative potential. Integration of metabolic and mechanical signals has emerged as a critical determinant of successful cardiomyocyte reactivation, providing a mechanistic rationale for combinatorial therapeutic strategies. Nevertheless, despite remarkable progression in mechanistic understanding and proof-of-concept studies, cardiac regeneration protocols advanced to robust clinical validation or pharmacal application have yet to be developed. This review provides a historical and biologically grounded synthesis of preclinical advances in cardiac repair, regeneration and cardiomyocyte reprogramming, with particular emphasis on translational feasibility and clinical applicability. Current strategies and preclinical trial outcomes are summarized to construct a readiness framework that maps the developmental maturity of each approach. Finally, the review highlights existing biological and technical barriers, as well as emerging opportunities poised to shape the future of cardiac regenerative medicine.

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We report on two patients who have a mitochondrial myopathy, encephalopathy, lactic acidosis, and recurrent cerebral insults that resemble strokes (MELAS). These two and nine other reported patients share the following features: ragged red fibers evident on muscle biopsy, normal early development, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness. Lactic acidemia is a common finding. We believe that MELAS represents a distinctive syndrome and that it can be differentiated from two other clinical disorders that also are associated with mitochondrial myopathy and cerebral disease: Kearns-Sayre syndrome and the myoclonus epilepsy ragged red fiber syndrome. Existing information suggests that MELAS is transmitted by maternal inheritance. The ragged red fibers suggest an abnormality of the electron transport system, but the precise biochemical disorders in these three clinical syndromes remain to be elucidated.

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Based on the hypothesis that mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) are caused by impaired vasodilation in an intracerebral artery, the authors evaluated the effects of administering l-arginine, a nitric oxide precursor. Patients were administered L-arginine intravenously at the acute phase or orally at the interictal phase. L-arginine infusions significantly improved all strokelike symptoms, suggesting that oral administration within 30 minutes of a stroke significantly decreased frequency and severity of strokelike episodes.

Intramuscular blood vessels were examined with succinate dehydrogenase stain in skeletal muscle biopsy specimens from 6 patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Almost all arteries had large granular deposits with high succinate dehydrogenase activity in their walls. Electron microscopic examination of serial frozen sections of these biopsies showed that the smooth muscle cells of the strongly succinate dehydrogenase-reactive blood vessels contained markedly proliferated mitochondria, characteristic of patients with MELAS. The presence of strongly succinate dehydrogenase-reactive blood vessels in muscle biopsy specimens provides an important clue toward understanding the underlying pathogenetic mechanism in patients with MELAS as well as another approach to the diagnosis of this disorder.

Electron microscopic examination of muscle specimens taken at biopsy in 6 patients with complex I deficiency and 1 patient with an unknown primary chemical defect who had the clinical characteristics of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) revealed striking abnormalities in blood vessels in 5. Abnormalities consisted of an increased number of enlarged mitochondria with complicated cristae in the pericytes of capillaries, endothelial cells, and smooth muscle cells of the small arteries, including terminal arterioles and precapillary sphincters, predominantly in smooth muscle cells. On statistical analysis, the number of mitochondria and the ratio of mitochondrial area to the total area of the smooth muscle cells were increased approximately tenfold (p less than 0.001). Although stroke-like episodes were not present, similar mitochondrial abnormalities in blood vessels were found in 1 patient who had the encephalomyopathic form of complex IV deficiency and in 2 patients in whom the primary chemical defects could not be clearly defined. Such abnormalities in small arteries might be responsible for the occasional occurrence of transient cerebral ischemia causing stroke-like episodes and progressive mental deterioration.

The primary cause for strokelike episodes in young patients with MELAS (myopathy, encephalopathy, lactic acidosis, and strokelike episodes)—whether mitochondrial cytopathy, angiopathy, or both—remains controversial. Based on a hypothesis that strokelike episodes in MELAS are caused by segmental impairment of vasodilation in intracerebral arteries, we administered l-arginine to three patients with MELAS in the acute phase of stroke (within 1 hour of onset) and evaluated effects on clinical course, biochemical measurements, and functional cerebral hemodynamics according to 99mTc-ECD SPECT.

### Patients.

Patient 1 was a 17-year-old woman referred to the hospital for periodic vomiting, hemiconvulsion, and short stature (below 2.7 SD). Patient 2 was an 18-year-old woman who was admitted to the hospital for generalized muscle weakness, periodic vomiting, hemiparesis, and short stature (below 1.5 SD). Patient 3 was a 15-year-old boy referred to our hospital for hemiblindness, hemiconvulsions, vomiting, and short stature (below 2.8 SD).

All patients showed extensive calcification in the basal ganglia, lactic acidosis (3.8 to 5.6 mmol/L; normal range …

We describe the clinical, imaging, and pathologic findings in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). The patient experienced her first stroke-like episode at age forty-four. Brain MRI, obtained at symptom onset, at 3 weeks, and at 1 year, revealed migrating T2-weighted hyperintensities in the temporal/parietal and occipital cortices and later revealed atrophy. Abnormal cerebrovascular reserve was evident on xenon/CT four days after the first MRI. MR spectroscopy at 1 year revealed increased lactate in both the occipital and temporal lobes. Histologic sections demonstrated spongy degeneration of the cortex that was most prominent at the crests of the gyri. Electron microscopy of the blood vessels showed increased numbers of abnormal mitochondria within the vascular smooth muscle and in endothelial cells. We hypothesize that the stroke-like episodes in MELAS may be due to impaired autoregulation secondary to the impaired metabolic activity of mitochondria in the endothelial and smooth muscle cells of blood vessels.

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Introduction: Mitochondrial diseases are multisystem disorders in which defects in oxidative phosphorylation disrupt cellular bioenergetics and redox signaling across the vasculature and heart. Because mitochondrial function is closely linked to endothelial nitric oxide (NO) production, we hypothesized that mitochondrial diseases manifest as a NO-deficiency endotheliopathy affecting conduit and microvascular function. To evaluate this, we performed a systematic review with quantitative synthesis of human studies reporting vascular reactivity, biochemical NO production, or myocardial metabolic imaging, aiming to define the magnitude of impairment and responsiveness to NO-precursor therapy (l-arginine or l-citrulline). Methods: ). Quantitative synthesis used Hedges g for between-group comparisons and standardized mean change (SMC) for within-subject responses. Risk of bias was evaluated using ROBINS-I and a modified Newcastle-Ottawa Scale. Results: Seven studies met these inclusion criteria, comprising 76 mitochondrial-disease subjects and 81 controls (ages 8-63 years). Across all vascular and metabolic domains, mitochondrial disease was associated with marked endothelial and bioenergetic impairment. Macro- and microvascular dysfunction, reflected by reduced FMD, RHI, and PLM hyperemia, demonstrated severe endothelium-specific abnormalities. Biochemical assays showed diminished NO synthesis. Myocardial PET imaging revealed reduced oxidative rate constants and increased energetic inefficiency despite preserved perfusion. Nitric oxide synthesis-precursor therapy was associated with improved endothelial reactivity (increased FMD, RHI, and ASR NOm) and significant, modest improvements in myocardial oxidative metabolism, consistent with partial restoration of endothelial NO signaling. Effect sizes collectively supported a reversible NO-deficiency endotheliopathy. The risk-of-bias assessment indicated moderate-to-good methodological quality, with limitations primarily related to small sample sizes and nonrandomized designs. Conclusions: Mitochondrial disease is characterized by significant impairments in vascular reactivity, NO signaling, and myocardial bioenergetics. Improvements in endothelial function and NO synthesis following l-arginine or l-citrulline supplementation are consistent with a role for impaired endothelial NO signaling in the vascular manifestations of mitochondrial disease. These findings highlight the vascular endothelium as a potential therapeutic target and underscore the need for future clinical intervention trials that use standardized vascular and bioenergetic endpoints.

Background: Primary mitochondrial disease (PMD) are genetic disorders characterized by impaired oxidative metabolism and microvascular abnormalities that contribute to the myopathy. Objectives: This study evaluates the feasibility and utility of contrast-enhanced ultrasound (CEUS) for quantifying skeletal muscle perfusion in patients with PMD. In addition, we assessed exercise-induced changes following cardiopulmonary exercise testing (CPET) to characterize dynamic vascular responses. Design: Prospective pilot feasibility study. Methods: We enrolled genetically confirmed PMD and healthy control participants with ability to complete the CPET protocol. CEUS of the vastus lateralis muscle was performed at rest and following CPET. Imaging parameters were standardized across all CEUS scans, with a fixed mechanical index of 0.13. Perfusion parameters, including perfusion index (PI), peak enhancement (PE), and area under the curve (AUC) were quantified using delta projection analysis, and compared between PMD and control participants, and within each group, pre- and post-exercise. Results: A total of 5 PMD and 5 control participants were evaluated. At rest, CEUS demonstrated a trend in higher muscle perfusion in PMD as compared to control participants on comparing PI (13.7 ± 2.7 vs. 10.7 ± 3.2; p = 0.42), PE (24.9 ± 11.5 vs. 14.3 ± 6.8; p = 0.22), and AUC (95,253.4 ± 35,072.8 vs. 73,591.2 ± 32,820.6; p = 0.31), which did not reach statistical significance, likely in part due to the small cohort size. Following CPET, PMD participants demonstrated exaggerated percentage increases in PI (+21.1% vs. +16.0%), PE (+11.2% vs. +7.6%), and AUC (+20.2% vs. +12.5%) as compared to control participants. Within group analysis revealed a significant post-exercise increase in AUC among PMD participants (p = 0.01) but did not reach significance in control participants. Conclusion: This is the first study to demonstrate the feasibility and utility of conducting CEUS to assess skeletal muscle perfusion in ambulatory PMD patients. The distinct perfusion patterns and exaggerated exercise-induced responses observed in PMD as compared to control participants suggest that reactive hyperemia occurs in PMD at rest and is further exaggerated by exercise. CEUS may serve as a sensitive tool for detecting microvascular alterations in PMD.

Background: Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes (MELAS) is rare in people over 40 years of age, and gastrointestinal complications of MELAS are also rare, especially Chronic Intestinal Pseudo-Obstruction (CIPO). Case Presentation: This report describes a 60 years old MELAS patient with a mutation rate of only 6.29% in the m.3243A>G gene, accompanied by CIPO. After treatment, MELAS symptoms can be controlled, but intestinal obstruction recurs and worsens. At present, patients fast and rely on intravenous nutrition to sustain their lives. Discussion: The low proportion of m.3243A>G mutations in patients may be related to their advanced age, but the high or low proportion of gene mutations detected in blood samples is not related to the severity of symptoms. MELAS combined with CIPO is rare and different from other intestinal obstructions. CIPO has no cause of mechanical intestinal obstruction and may be related to dysfunction of smooth muscle mitochondria or involvement of the enteric nervous system. Conclusion: For complications of MELAS beyond the nervous system, early consideration should be given to the possibility of MELAS. Early genetic testing has important clinical significance for the treatment and prognosis of patients. This article will provide a literature review on the multi system performance of MELAS.

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Mitochondrial heteroplasmy represents a fundamental determinant of mitochondrial function and disease, yet its consequences vary across different tissues. Although mitotic tissues possess mechanisms, such as cell division and mitochondrial turnover, to dilute or remove deleterious variants, postmitotic tissues lack this renewal capacity and are disproportionately vulnerable. Neuromuscular and neurodegenerative disorders have illustrated the impact of heteroplasmic mutations, but the (postmitotic) heart remains underexplored. Current reliance on blood-derived samples provides only an indirect view of cardiac heteroplasmy, highlighting the need for alternative approaches, such as endomyocardial biopsies and human induced pluripotent stem cell-derived cardiomyocytes. Expanding cardiac-focused research is essential for identification, clarifying pathogenesis, improving risk stratification, and guiding patient monitoring. Emerging therapies, including mitochondrial transplantation and mitochondrial-targeted DNA editing, demonstrate potential to modulate heteroplasmy and restore equilibrium. Integrating these strategies with precision medicine will be vital for addressing tissue-specific vulnerabilities. Ultimately, bridging the gap in cardiac heteroplasmy research will be critical for translating basic mitochondrial biology into meaningful clinical advances.

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Mitochondrial complex I is the first and largest enzyme of the mitochondrial respiratory chain and thus plays a crucial role in cellular energy metabolism. Defects in the mitochondrial respiratory chain, and in particular CI deficiency, are the primary cause of human mitochondrial associated diseases, which most often presents as severe neurometabolic disorders with fatal outcome. Up to this date the diagnosis and treatment of CI deficiency-associated diseases is challenging, only limited symptomatic therapies exist and no cures are available. This review aims at summarizing current knowledge on the genetic basis of CI deficiency-associated diseases and available experimental disease models. Most common human disorders caused by CI deficiency range from Leigh syndrome to MELAS and LHON, all characterized by genetic and symptomatic heterogeneity. So far, in vivo studies on non-mammalian organisms and mouse models, as well as in vitro studies on patient derived fibroblasts, cybrids and human-induced pluripotent stem cells have mainly facilitated the research of CI deficiency. These model systems provide insights on molecular mechanisms in mitochondrial disease and approaches for potential therapeutic intervention strategies. However, current research is limited by translational relevance of existing disease models, varying degrees of heteroplasmy and tissue specific effects characteristic of mitochondrial diseases, so that basic disease mechanisms still remain poorly understood. To overcome these challenges there is an urgent need for in vivo and in vitro human relevant models to aid the development of effective therapeutic interventions and potential cures of CI deficiency-associated diseases.

Since the discovery of mitochondrial DNA (mtDNA) diseases almost 40 years ago, large numbers of diseases have been linked to mutations in both mtDNA and nuclear DNA (nDNA) genes that perturb the mitochondrial energy-generating system, oxidative phosphorylation (OXPHOS). Mitochondrial dysfunction is being implicated not only in rare primary mitochondrial diseases but also a wide range of common diseases, yet the availability of effective mitochondrial therapies remains limited. One potential source of mitochondrial therapeutic approaches is Traditional Chinese Medicine (TCM). TCM emphasizes the health-preservation philosophy and practical experience centered around the concept of “Qi”, or vital force, and has generated Qi-oriented therapies over the past several thousand years. We propose that various properties and functions attributed to Qi may be explained by modulation of mitochondrial bioenergetics, the interplay between OXPHOS and fatty acid oxidation versus glycolysis and the pentose phosphate pathway (PPP), and the mitochondrial regulation of the immune system through mitochondrial reactive oxygen species (mROS). Hence, TCM therapeutics may provide approaches for treating the increasing spectrum of mitochondria associated diseases.