Preclinical models of mitochondrial dysfunction: mtDNA and nuclear-encoded regulators in diverse pathologies

Frontiers in Aging · 2025-06-23 · 7 citations

Mitochondrial-driven diseases encompass a diverse group of single-gene and complex disorders, all linked to mitochondrial dysfunction, with significant impacts on human health. While there are rare mitochondrial diseases in which the primary defect resides in mutations in mitochondrial DNA, it is increasingly clear that acquired mitochondrial dysfunction, both genetically- and epigenetically-mediated, complicates common complex diseases, including diabetes, cardiovascular disease and ischemia reperfusion injury, cancer, pulmonary hypertension, and neurodegenerative diseases. It is also recognized that mitochondrial abnormalities not only act by altering metabolism but, through effects on mitochondrial dynamics, can regulate numerous cellular processes including intracellular calcium handling, cell proliferation, apoptosis and quality control. This review examines the crucial role of preclinical models in advancing our understanding of mitochondrial genetic contributions to these conditions. It follows the evolution of models of mitochondrial-driven diseases, from earlier in vitro and in vivo systems to the use of more innovative approaches, such as CRISPR-based gene editing and mitochondrial replacement therapies. By assessing both the strengths and limitations of these models, we highlight their contributions to uncovering disease mechanisms, identifying therapeutic targets, and facilitating novel discoveries. Challenges in translating preclinical findings into clinical applications are also addressed, along with strategies to enhance the accuracy and relevance of these models. This review outlines the current state of the field, the future trajectory of mitochondrial disease modeling, and its potential impact on patient care.

Platelet and skeletal muscle mitochondrial bioenergetics correlate in a murine model of Type II Diabetes

Free Radical Biology and Medicine · 2025-10-30

Multi-tissue metabolomics reveal mtDNA- and diet-specific metabolite profiles in a mouse model of cardiometabolic disease

Redox Biology · 2025-02-14 · 6 citations

RATIONALE: Excess consumption of sugar- and fat-rich foods has heightened the prevalence of cardiometabolic disease, which remains a driver of cardiovascular disease- and type II diabetes-related mortality globally. Skeletal muscle insulin resistance is an early feature of cardiometabolic disease and is a precursor to diabetes. Insulin resistance risk varies with self-reported race, whereby African-Americans have a greater risk of diabetes development relative to their White counterparts. Self-reported race is strongly associated with mitochondrial DNA (mtDNA) haplogroups, and previous reports have noted marked differences in bioenergetic and metabolic parameters in cells belonging to distinct mtDNA haplogroups, but the mechanism of these associations remains unknown. Additionally, distinguishing nuclear DNA (nDNA) and mtDNA contributions to cardiometabolic disease remains challenging in humans. The Mitochondrial-Nuclear eXchange (MNX) mouse model enables in vivo preclinical investigation of the role of mtDNA in cardiometabolic disease development, and has been implemented in studies of insulin resistance, fatty liver disease, and obesity in previous reports. METHODS: MNX mice, were fed sucrose-matched high-fat (45% kcal fat) or control diet (10% kcal fat) until 12 weeks of age (n = 5/group). Mice were weighed weekly and total body fat was collected at euthanasia. Gastrocnemius skeletal muscle and plasma metabolomes were characterized using untargeted dual-chromatography mass spectrometry; both hydrophilic interaction liquid chromatography (HILIC) and C18 columns were used, in positive- and negative-ion modes, respectively. RESULTS: was associated with branched chain amino acid metabolite co-expression. CONCLUSIONS: These results reveal novel nDNA-mtDNA interactions that drive significant changes in metabolite levels. Alterations to key metabolites involved in mitochondrial bioenergetic dysfunction and electron transport chain activity are implicated in elevated beta-oxidation during high-fat diet feeding; abnormally elevated rates of beta-oxidation may be a key driver of insulin resistance. The results reported here support the hypothesis that mtDNA influences cardiometabolic disease-susceptibility by modulating mitochondrial function and metabolic pathways.

Platelet bioenergetics correlate with skeletal muscle respiration in a murine model of type II diabetes

Frontiers in Molecular Biosciences · 2025-11-14 · 2 citations

Mitochondrial bioenergetic research in skeletal muscle is limited by the need for biopsies. We executed a proof-of-concept study to evaluate whether blood platelets could serve as a minimally invasive surrogate for skeletal muscle mitochondrial respiration in mice. Using Seahorse extracellular flux analysis, platelet respiration was measured in healthy C57BL/6J and leptin receptor-null db/db mice, while high-resolution respirometry (Oroboros O2k) assessed mitochondrial function in white gastrocnemius muscle of the same animals. A critical component of this study was extensive methodological optimization for platelet bioenergetics analysis in mice. We provide comprehensive methodological details and guiding principles for performing Seahorse bioenergetic assays on mouse platelets. Our foundational findings also suggest platelet mitochondria can reflect tissue-level mitochondrial health, pointing to a potential “liquid biopsy” approach for assessing metabolic status. Multiple key metrics of respiration showed significant correlations between platelets and muscle in the same animals, indicating that platelet bioenergetic profiles mirror the metabolic status of skeletal muscle in healthy and genetically diabetic mice. This work lays the conceptual and methodological foundation for future studies in human metabolic diseases where muscle bioenergetic dysfunction is implicated but current methods are not implementable for clinical surveillance. This study provides foundational proof-of-concept in healthy and diabetic mice, motivating validation in human studies as the next step toward biomarker development and precision medicine strategies.

Metabolic Dysfunction‐Associated Steatotic Liver Disease ( <scp>MASLD</scp> ): Mechanisms, Clinical Implications and Therapeutic Advances

Endocrinology Diabetes & Metabolism · 2025-11-01 · 33 citations

INTRODUCTION: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide, affecting ~25%-30% of the adult population, with higher prevalence observed in individuals with obesity and type 2 diabetes. Among reported MASLD cases, prevalence is consistently higher in men than in women, and global incidence has risen by ~50% over the past two decades, mirroring the global rise in obesity and metabolic syndrome. MASLD encompasses a spectrum of hepatic pathologies ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Despite its high prevalence, the heterogeneity in disease progression and relative absence of approved pharmacological therapies pose challenges for effective clinical management. METHODS AND RESULTS: This review synthesises current literature on MASLD across epidemiology, pathophysiology, clinical presentation and treatment. Key molecular mechanisms, including lipid metabolism dysregulation, insulin resistance and mitochondrial dysfunction, are examined with a focus on understanding the basis for progression to metabolic dysfunction-associated steatohepatitis (MASH). Clinical manifestations, diagnostic tools and risk stratification systems for MASLD are summarised. Current and emerging therapies such as lifestyle interventions, pharmacological agents and microbiome-targeted strategies are reviewed. The review also highlights ongoing challenges, including diagnostic limitations, disease heterogeneity and disparities in care. CONCLUSION: MASLD is a complex, multifactorial liver disease with a growing public health impact, driven by the rising prevalence of metabolic syndrome. Mitochondrial dysfunction is a critical nexus linking genetic susceptibility to metabolic stress and inflammatory responses. Preclinical models that capture these mitochondrial contributions are vital for therapeutic discovery and for advancing personalised medicine approaches in MASLD care.

Redox Homeostasis in Metabolic Syndrome and Type II Diabetes: Role of Skeletal Muscle and Impact of Gold-Standard Treatments

International Journal of Molecular Sciences · 2025-10-24 · 3 citations

Metabolic syndrome and type II diabetes pose a significant international health burden, with the latter characterized by insulin resistance. Patients must rely on therapies that maintain glucose homeostasis when endogenous systems become dysfunctional. Skeletal muscle, as the largest insulin-sensitive tissue in the body, plays a critical role in maintaining glucose homeostasis. During disease progression, chronic nutrient overload shifts redox balance to a pro-oxidant state, further exacerbating metabolic dysfunction. First-line treatments, such as metformin and insulin, along with newly adopted incretin-based therapies, modulate the redox state of skeletal muscle. This review explores how the redox state of healthy skeletal muscle is altered throughout metabolic disease progression and how these changes contribute to a worsening phenotype. We also highlight how each class of regularly prescribed medications targets redox-sensitive systems in skeletal muscle, identifying literature gaps and areas for future investigation.

Multi-Tissue Metabolomics Reveal mtDNA- and Diet-Specific Metabolite Profiles in a Mouse Model of Cardiometabolic Disease

bioRxiv (Cold Spring Harbor Laboratory) · 2024

• Internal medicine
• Biology
• Endocrinology

Abstract Rationale Excess consumption of sugar- and fat-rich foods has heightened the prevalence of cardiometabolic disease, which remains a driver of cardiovascular disease- and type II diabetes-related mortality globally. Skeletal muscle insulin resistance is an early feature of cardiometabolic disease and is a precursor to diabetes. Insulin resistance risk varies with self-reported race, whereby, African-Americans have a greater risk of diabetes development relative to their White counterparts. Self-reported race is strongly associated with mitochondrial DNA (mtDNA) haplogroups, and previous reports have noted marked differences in bioenergetic and metabolic parameters in cells belonging to distinct mtDNA haplogroups, but the mechanism of these associations remains unknown. Additionally, distinguishing nuclear DNA (nDNA) and mtDNA contributions to cardiometabolic disease remains challenging in humans. The Mitochondrial-Nuclear eXchange (MNX) mouse model enables in vivo preclinical investigation of the role of mtDNA in cardiometabolic disease development, and has been implemented in studies of insulin resistance, fatty liver disease, and obesity in previous reports. Methods Six-week-old male C57 nDNA :C57 mtDNA and C3H nDNA :C3H mtDNA wild-type mice, and C57 nDNA :C3H mtDNA and C3H nDNA :C57 mtDNA MNX mice, were fed sucrose-matched high-fat (45% kcal fat) or control diet (10% kcal fat) until 12 weeks of age (n = 5/group). Mice were weighed weekly and total body fat was collected at euthanasia. Gastrocnemius skeletal muscle and plasma metabolomes were characterized using untargeted dual-chromatography mass spectrometry; both hydrophilic interaction liquid chromatography (HILIC) and C18 columns were used, in positive- and negative-ion modes, respectively. Results Comparative analyses between nDNA-matched wild-type and MNX strains demonstrated significantly increased body fat percentage in mice possessing C57 mtDNA regardless of nDNA background. High-fat diet in mice possessing C57 mtDNA was associated with differential abundance of phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines, and glucose. Conversely, high-fat diet in mice possessing C3H mtDNA was associated with differential abundance of phosphatidylcholines, cardiolipins, and alanine. Glycerophospholipid metabolism and beta-alanine signaling pathways were enriched in skeletal muscle and plasma, indicating mtDNA-directed priming of mitochondria towards oxidative stress and increased fatty acid oxidation in C57 nDNA :C57 mtDNA wild-type and C3H nDNA :C57 mtDNA MNX mice, relative to their nDNA-matched counterparts. In mtDNA-matched mice, C57 mtDNA was associated with metabolite co-expression related to the pentose phosphate pathway and sugar-related metabolism; C3H mtDNA was associated with branched chain amino acid metabolite co-expression. Conclusions These results reveal novel nDNA-mtDNA interactions that drive significant changes in metabolite levels. Alterations to key metabolites involved in mitochondrial bioenergetic dysfunction and electron transport chain activity are implicated in elevated beta-oxidation during high-fat diet feeding; abnormally elevated rates of beta-oxidation may be a key driver of insulin resistance. The results reported here support the hypothesis that mtDNA influences cardiometabolic disease-susceptibility by modulating mitochondrial function and metabolic pathways.

Клинико-морфологические изменения слизистой оболочки желудка у больных хроническим гастритом, ассоциированным с хроническим пародонтитом

Экспериментальная и клиническая гастроэнтерология · 2013-01-01

Клинико-морфологические различия повреждения верхних отделов ЖКТ и некоторые биохимические показатели крови у женщин и мужчин больных хроническим гепатитом и циррозом печени

Экспериментальная и клиническая гастроэнтерология · 2013-01-01

Author Index Vol. 20, 1978

Cytogenetics and Cell Genetics · 2008-05-06