#Optic Atrophy 1 (OPA1)

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Mitochondrial Dysfunction in Type 2 Diabetes

Introduction

Mitochondria, essential for cellular energy metabolism, play a crucial role in bioenergetics and metabolic homeostasis. Mitochondrial dysfunction has been implicated as a key pathophysiological factor in Type 2 Diabetes Mellitus (T2DM), contributing to insulin resistance, metabolic inflexibility, and beta-cell dysfunction. This review explores the intricate mechanisms underlying mitochondrial impairments in T2DM, including defective oxidative phosphorylation, disrupted mitochondrial dynamics, impaired mitophagy, and excessive reactive oxygen species (ROS) generation, with a focus on potential therapeutic interventions targeting mitochondrial pathways.

Mechanistic Insights into Mitochondrial Dysfunction in T2DM

1. Defective Oxidative Phosphorylation and ATP Synthesis

Mitochondrial oxidative phosphorylation (OXPHOS) occurs through the electron transport chain (ETC), comprising Complexes I-IV and ATP synthase (Complex V). In T2DM, evidence suggests a downregulation of mitochondrial ETC activity, particularly in Complex I (NADH:ubiquinone oxidoreductase) and Complex III (cytochrome bc1 complex), leading to reduced ATP synthesis. This dysfunction is often linked to compromised NADH oxidation and inefficient proton gradient formation, resulting in cellular energy deficits and impaired insulin-stimulated glucose uptake.

2. Elevated Reactive Oxygen Species (ROS) and Oxidative Stress

Mitochondria are a primary source of ROS, predominantly generated at Complex I and Complex III during electron leakage. In T2DM, excess substrate influx due to hyperglycemia leads to mitochondrial overactivation, driving excessive ROS production. Elevated ROS induces oxidative damage to mitochondrial DNA (mtDNA), lipids, and proteins, disrupting mitochondrial integrity and function. Oxidative stress further impairs insulin signaling by activating stress-responsive kinases such as c-Jun N-terminal kinase (JNK) and IκB kinase (IKK), contributing to systemic insulin resistance.

3. Mitochondrial Biogenesis and Transcriptional Dysregulation

Mitochondrial biogenesis is regulated by the transcriptional coactivator Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), which modulates downstream transcription factors such as Nuclear Respiratory Factors (NRF-1/NRF-2) and Mitochondrial Transcription Factor A (TFAM). In T2DM, PGC-1α expression is downregulated, impairing mitochondrial biogenesis and reducing mitochondrial density, leading to decreased oxidative capacity in metabolically active tissues like skeletal muscle and liver.

4. Disrupted Mitochondrial Dynamics and Mitophagy

Mitochondrial quality control is maintained through dynamic fission and fusion processes. Fission, mediated by Dynamin-related protein 1 (Drp1), is necessary for mitochondrial fragmentation and mitophagy, while fusion, regulated by Mitofusin 1/2 (Mfn1/2) and Optic Atrophy 1 (OPA1), maintains mitochondrial integrity. In T2DM, an imbalance favoring excessive fission leads to mitochondrial fragmentation, impairing energy metabolism and exacerbating insulin resistance. Moreover, defective mitophagy, regulated by PTEN-induced kinase 1 (PINK1) and Parkin, results in the accumulation of dysfunctional mitochondria, further aggravating metabolic dysfunction.

Implications of Mitochondrial Dysfunction in T2DM Pathophysiology

1. Skeletal Muscle Insulin Resistance

Skeletal muscle accounts for ~80% of postprandial glucose uptake, relying on mitochondrial ATP production for insulin-mediated glucose transport. Impaired mitochondrial function in muscle cells reduces oxidative phosphorylation efficiency, promoting a shift towards glycolysis and lipid accumulation, ultimately leading to insulin resistance.

2. Pancreatic Beta-Cell Dysfunction

Mitochondrial ATP production is essential for insulin secretion in pancreatic beta cells. ATP-sensitive potassium channels (K_ATP) regulate glucose-stimulated insulin secretion (GSIS), with ATP/ADP ratios dictating channel closure and depolarization-induced insulin exocytosis. In T2DM, mitochondrial dysfunction leads to inadequate ATP generation, impairing GSIS and reducing insulin secretion capacity. Additionally, oxidative stress-induced beta-cell apoptosis contributes to progressive loss of beta-cell mass.

3. Hepatic Mitochondrial Dysfunction and Lipid Dysregulation

Mitochondrial dysfunction in hepatocytes contributes to hepatic insulin resistance and non-alcoholic fatty liver disease (NAFLD). Impaired fatty acid oxidation due to dysfunctional mitochondria leads to lipid accumulation, exacerbating hepatic insulin resistance and systemic metabolic dysregulation.

Therapeutic Strategies Targeting Mitochondrial Dysfunction

1. Exercise-Induced Mitochondrial Adaptation

Physical activity upregulates PGC-1α expression, enhancing mitochondrial biogenesis and oxidative metabolism. High-intensity interval training (HIIT) and endurance exercise improve mitochondrial efficiency and reduce oxidative stress, mitigating insulin resistance in T2DM patients.

2. Pharmacological Modulation of Mitochondrial Function

Metformin: Enhances mitochondrial complex I activity, reducing hepatic gluconeogenesis and oxidative stress.

Thiazolidinediones (TZDs): Activate PPAR-γ, promoting mitochondrial biogenesis and improving insulin sensitivity.

Mitochondria-targeted Antioxidants: Agents like MitoQ, SkQ1, and SS-31 reduce mitochondrial ROS, preventing oxidative damage and preserving mitochondrial function.

3. Nutritional and Metabolic Interventions

Ketogenic and Low-Carb Diets: Enhance mitochondrial fatty acid oxidation, reducing lipid accumulation and improving metabolic flexibility.

Intermittent Fasting: Induces mitochondrial biogenesis and autophagy, improving metabolic homeostasis.

Nutraceuticals: Coenzyme Q10, resveratrol, and nicotinamide riboside (NR) enhance mitochondrial function and energy metabolism.

4. Emerging Gene and Cellular Therapies

Gene Therapy: Targeted upregulation of PGC-1α and TFAM to restore mitochondrial function.

Mitochondrial Transplantation: Direct transfer of healthy mitochondria to replace dysfunctional ones, an emerging frontier in metabolic disease management.

Conclusion

Mitochondrial dysfunction is a central determinant in the pathogenesis of T2DM, affecting insulin signaling, glucose metabolism, and lipid homeostasis. Targeting mitochondrial pathways through exercise, pharmacological agents, dietary modifications, and emerging gene therapies offers promising avenues for improving metabolic health in T2DM. 

[tumimmtxpapers]

OPA1-anchored PKA phosphorylates perilipin 1 on S522 and S497 in adipocytes differentiated from human adipose stem cells.

Related Articles OPA1-anchored PKA phosphorylates perilipin 1 on S522 and S497 in adipocytes differentiated from human adipose stem cells. Mol Biol Cell. 2018 Apr 24;:mbcE17090538 Authors: Rogne M, Chu DT, Küntziger TM, Mylonakou MN, Collas P, Tasken K Abstract Optic atrophy 1 (OPA1) is the A-kinase anchoring protein (AKAP) targeting the pool of PKA responsible for perilipin 1 phosphorylation, a gatekeeper for lipolysis. However, the involvement of OPA1-bound PKA in the downstream regulation of lipolysis is unknown. Here, we show upregulation and relocation of OPA1 from mitochondria to lipid droplets during adipocytic differentiation of human adipose stem cells (hASCs). We employed various biochemical and immunological approaches to demonstrate that OPA1-bound PKA phosphorylates perilipin 1 at S522 and S497 upon lipolytic stimulation. We show that the first 30 amino acids of OPA1 are essential for its lipid droplet localization as is OMA1-dependent processing. Finally, our results indicate that presence of OPA1 is necessary for lipolytic phosphorylation of downstream targets. Our results show for the first time how OPA1 mediates adrenergic control of lipolysis in human adipocytes by regulating phosphorylation of perilipin 1. PMID: 29688805 [PubMed - as supplied by publisher] http://dlvr.it/QQn0mv

[neurogenpapers]

Phyllanthus urinaria's Inhibition of Human Osteosarcoma Xenografts Growth in Mice is Associated with Modulation of Mitochondrial Fission/Fusion Machinery.

PubMed: Related Articles Phyllanthus urinaria's Inhibition of Human Osteosarcoma Xenografts Growth in Mice is Associated with Modulation of Mitochondrial Fission/Fusion Machinery. Am J Chin Med. 2016;44(7):1507-1523 Authors: Huang ST, Huang CC, Sheen JM, Lin TK, Liao PL, Huang WL, Wang PW, Liou CW, Chuang JH Abstract Osteosarcoma is an aggressive bone cancer arising from primitive transformed cells of mesenchymal origin to form malignant osteoid. Phyllanthus urinaria [Formula: see text]P. urinaria[Formula: see text] is a widely used folk medicine in cancer treatment, however the mechanism of P. urinaria inhibited human osteosarcoma is unclear. The present study was aimed at investigating the antitumoral effects of an aqueous P. urinaria on human osteosarcoma in vivo and the related underlying mechanisms, mainly focusing on mitochondrial dynamic dysfunction. Our results showed that oral administration of P. urinaria to mice led to significant inhibition of tumor development without substantial changes to body weight or major organs. Histological examinations with H&E, Giemsa, and Masson trichrome stains confirmed inhibition of tumor growth by the P. urinaria treatment. Immunohistochemical staining of proliferation markers antigen KI-67 (Ki67) and proliferating cell nuclear antigen (PCNA), as well as a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated a decrease of tumor proliferation and an increase of apoptosis, which was associated with the modulation of B-cell lymphoma 2 (Bcl-2) family activating the caspase cascade in the P. urinaria-treated mice. The neovascularization marker cluster of differentiation 31 (CD31) was inhibited in P. urinaria-treated xenografts, implicating the potential anti-angiogenic effect of P. urinaria. P. urinaria treatment resulted in a significant decrease in the mitochondrial fusion proteins, including mitofusin 1/2 (Mfn1/2) and optic atrophy type 1 (Opa1), as well as an increase in the fission protein dynamin-related protein 1 (Drp1). The results of this study suggest mitochondrial dysfunction is associated with dynamic change that is involved in the apoptosis and anti-angiogenesis elicited by P. urinaria. PMID: 27776427 [PubMed - indexed for MEDLINE] http://dlvr.it/NDX2kT

[neurogenpapers]

Association between Mitofusin 2 Gene Polymorphisms and Late-Onset Alzheimer's Disease in the Korean Population.

PubMed: Related Articles Association between Mitofusin 2 Gene Polymorphisms and Late-Onset Alzheimer's Disease in the Korean Population. Psychiatry Investig. 2017 Jan;14(1):81-85 Authors: Kim YJ, Park JK, Kang WS, Kim SK, Han C, Na HR, Park HJ, Kim JW, Kim YY, Park MH, Paik JW Abstract OBJECTIVE: Mitochondrial dysfunction is a prominent and early feature of Alzheimer's disease (AD). The morphologic changes observed in the AD brain could be caused by a failure of mitochondrial fusion mechanisms. The aim of this study was to investigate whether genetic polymorphisms of two genes involved in mitochondrial fusion mechanisms, optic atrophy 1 (OPA1) and mitofusin 2 (MFN2), were associated with AD in the Korean population by analyzing genotypes and allele frequencies. METHODS: One coding single nucleotide polymorphism (SNP) in the MFN2, rs1042837, and two coding SNPs in the OPA1, rs7624750 and rs9851685, were compared between 165 patients with AD (83 men and 82 women, mean age 72.3±4.41) and 186 healthy control subjects (82 men and 104 women, mean age 76.5±5.98). RESULTS: Among these three SNPs, rs1042837 showed statistically significant differences in allele frequency, and genotype frequency in the co-dominant 1 model and in the dominant model. CONCLUSION: These results suggest that the rs1042837 polymorphism in MFN2 may be involved in the pathogenesis of AD. PMID: 28096879 [PubMed - in process] http://dlvr.it/N8BbMk