Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis

Abstract

Type 2 diabetes mellitus (T2DM) is a systemic disease characterized by hyperglycemia, hyperlipidemia, and organismic insulin resistance. This pathological shift in both circulating fuel levels and energy substrate utilization by central and peripheral tissues contributes to mitochondrial dysfunction across organ systems. The mitochondrion lies at the intersection of critical cellular pathways such as energy substrate metabolism, reactive oxygen species (ROS) generation, and apoptosis. It is the disequilibrium of these processes in T2DM that results in downstream deficits in vital functions, including hepatocyte metabolism, cardiac output, skeletal muscle contraction, β-cell insulin production, and neuronal health. Although mitochondria are known to be susceptible to a variety of genetic and environmental insults, the accumulation of mitochondrial DNA (mtDNA) mutations and mtDNA copy number depletion is helping to explain the prevalence of mitochondrial-related diseases such as T2DM. Recent work has uncovered novel mitochondrial biology implicated in disease progressions such as mtDNA heteroplasmy, noncoding RNA (ncRNA), epigenetic modification of the mitochondrial genome, and epitranscriptomic regulation of the mtDNA-encoded mitochondrial transcriptome. The goal of this review is to highlight mitochondrial dysfunction observed throughout major organ systems in the context of T2DM and to present new ideas for future research directions based on novel experimental and technological innovations in mitochondrial biology. Finally, the field of mitochondria-targeted therapeutics is discussed, with an emphasis on novel therapeutic strategies to restore mitochondrial homeostasis in the setting of T2DM.

Mitochondrial adaptations to exercise do not require Bcl2‐mediated autophagy but occur with BNIP3/Parkin activation

“…Declines in skeletal muscle protein turnover rates are observed in metabolic diseases and with advancing age . Many metabolic and age‐associated pathological conditions are also associated with mitochondrial defects or dysfunction . Endurance exercise training improves mitochondrial oxidative function and whole‐body metabolic health, in part by increasing skeletal muscle mitochondrial abundance mediated by increases in mitochondrial biogenesis .…”

“…5,6 Many metabolic and age-associated pathological conditions are also associated with mitochondrial defects or dysfunction. 7,8 Endurance exercise training improves mitochondrial oxidative function and whole-body metabolic health, in part by increasing skeletal muscle mitochondrial abundance 9 mediated by increases in mitochondrial biogenesis. 10 Further understanding of mitochondrial protein turnover regulation could inform strategies to maintain skeletal muscle health and alleviate burdens of metabolic disease.…”

Type 2 diabetes – unmet need, unresolved pathogenesis, mTORC1-centric paradigm

“…Insulin resistance has been proposed to be driven by 'mitochondrial dysfunction' with decrease in mitochondria content, size, biogenesis, electron flux and oxidative phosphorylation, and increased oxidative stress [78,79]. Indeed, muscle insulin resistance with concomitant mitochondrial dysfunction has been verified in diabetes patients, obese prediabetic subjects, insulin-resistant lean non-diabetic off-springs of T2D parents, insulin-resistant non-diabetic elderly and T2D animal models, implying a putative causal relationship [62].…”

Impact of pharmacological agents on mitochondrial function: a growing opportunity?

“…Genetics also influences susceptibility to mitochondrial and metabolic dysfunction. For example, the mtDNA genetic variant at 16 189 from T to C has been associated with increased oxidative damage, altered antioxidant status and onset of type two diabetes [59][60][61]. Furthermore, different mtDNA haplogroups have been increasingly associated with individual susceptibility to toxic side effects observed in some patients [62][63][64][65][66].…”