Mitochondrial Proteostasis Links Diabetes and Sarcopenia: Cross-Scale Convergence from Experimental Models to Human Multi-Omics.

Sarcopenia in type 2 diabetes mellitus is increasingly recognized as a mechanistic consequence of chronic metabolic stress rather than mere age-related comorbidity. This review synthesizes evidence demonstrating how insulin resistance, hyperglycemia, lipotoxicity, and inflammation converge on skeletal muscle mitochondrial proteostasis to drive progressive decline. We evaluate seven pathway modules-mitochondrial dynamics, mitophagy, biogenesis, oxidative phosphorylation, nicotinamide adenine dinucleotide (NAD+)/sirtuin (SIRT)-linked regulation, protein import, and the mitochondrial unfolded protein response (UPRmt)-across an evidence map encompassing basic, clinical, and multi-omics studies. Dynamics and mitophagy represent mechanistically central quality-control nodes; their impairment permits dysfunctional organelle accumulation and promotes atrophic cascades. Direct evidence density, however, remains weighted toward oxidative phosphorylation and mitochondrial biogenesis. NAD+/SIRT-linked regulation, protein import fidelity, and UPRmt represent mechanistically upstream but comparatively underinvestigated signals. We propose a diabetes-centered framework where mitochondrial proteostasis failure mediates atrophy and reinforces insulin resistance via a self-amplifying feed-forward loop, supported by pathway responsiveness to coherent interventions. Human multi-omics data highlight network-level dysregulation rather than isolated defects, underscoring module-based biomarker strategies. Translationally, exercise remains the mechanistic cornerstone, while pathway-directed adjuncts-NAD+ precursor repletion, mitophagy modulators, and emerging pharmacotherapeutics-are warranted for patients with identifiable module-specific failure patterns.