Mitochondrial Integrated Stress Response (mtISR): Mechanistic Basis and Emerging Roles in Skeletal Muscle Pathophysiology

Mitochondria are dynamic organelles that maintain cellular homeostasis through complex mitonuclear communication networks. Among the retrograde signaling pathways linking mitochondrial dysfunction to nuclear gene expression, the mitochondrial integrated stress response (mtISR) has emerged as an important adaptive mechanism, although its chronic activation may contribute to disease progression. It is triggered by various stressors, including mitochondrial DNA (mtDNA) damage, impaired protein import, and metabolic imbalance and is primarily mediated through the eukaryotic translation initiation factor 2 alpha (eIF2α) kinases heme-regulated inhibitor kinase (HRI) and general control nonderepressible 2 (GCN2). Activation of this pathway suppresses global translation while selectively promoting activating transcription factor 4 (ATF4)-dependent transcriptional programs, leading to metabolic remodeling and induction of systemic mitokines. Although mtISR has been characterized in primary mitochondrial myopathies, secondary mitochondrial dysfunction in neuromuscular disorders suggests that mtISR-related pathways may also be activated in these conditions. This review summarizes the molecular mechanisms of mtISR and discusses its roles in skeletal muscle pathology.