When Mitochondrial Quality Control Is Overwhelmed: A Capacity–Burden Perspective on Type 2 Diabetes

Mitochondrial quality control (MQC) is essential for maintaining mitochondrial integrity, metabolic flexibility, and cellular homeostasis. Rather than functioning as isolated pathways, molecular repair and proteostasis, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis form an interconnected network that continuously detects, compensates for, removes, and replaces damaged mitochondrial components. In type 2 diabetes (T2D), chronic nutrient excess, metabolic stress, and low-grade inflammation disrupt this network. Increased metabolic flux and electron pressure within the respiratory chain promote excessive reactive oxygen species (ROS) production and oxidative damage to mitochondrial proteins, lipids, and mitochondrial DNA (mtDNA). Persistent stress challenges molecular repair capacity, alters the balance of mitochondrial fusion and fission, impairs mitophagic clearance, and compromises mitochondrial renewal. These abnormalities interact with one another, promoting the accumulation of dysfunctional mitochondria and establishing a self-reinforcing cycle of oxidative stress, inflammation, insulin resistance, and pancreatic β-cell dysfunction. This review examines the molecular mechanisms through which metabolic stress disrupts the MQC network in T2D and considers the tissue-specific consequences of impaired MQC. This further discusses established antidiabetic therapies and emerging mitochondria-targeted interventions that may modulate different components of the MQC network, including oxidative stress, molecular repair, mitochondrial dynamics, mitophagy, and biogenesis. By framing MQC as an integrated and interconnected network rather than a series of strictly sequential or hierarchical defenses, this review provides a framework for understanding how impaired MQC contributes to T2D pathogenesis and for identifying therapeutic strategies aimed at restoring mitochondrial and metabolic homeostasis.