Mitochondrial orchestration of PANoptosis: mechanisms, disease pathogenesis, and emerging therapeutic frontiers

Mitochondria, traditionally known as cellular powerhouses, are now recognized as central regulators of programmed cell death (PCD) and key players in disease pathogenesis. This review synthesizes current knowledge on mitochondrial mechanisms in PANoptosis-a convergent pathway integrating apoptosis, necroptosis, and pyroptosis-and their implications in diverse pathologies. Mitochondria govern intrinsic apoptosis via Bcl-2 family proteins and mitochondrial outer membrane permeabilization (MOMP), amplify necroptosis through RIPK1/RIPK3-driven ROS signaling, and indirectly regulate pyroptosis via inflammasome-mitochondria crosstalk. Dysfunctional mitochondria contribute to neurodegenerative diseases, cardiovascular disorders, cancer, and autoimmune/metabolic syndromes. Emerging therapies targeting mitochondrial pathways, such as Bcl-2 inhibitors, mPTP modulators, and ROS-inducing agents, demonstrate clinical promise in restoring cell death sensitivity and mitigating inflammation. By bridging molecular mechanisms with therapeutic innovations, this work underscores mitochondria as dynamic hubs of cellular fate and disease intervention.