Mitochondrial Dysfunction at the Crossroads of Necroptosis: Mechanisms, Molecular Mediators, and Therapeutic Opportunities

Abstract

The conceptual landscape of cell death has evolved beyond the traditional dichotomy of apoptosis and necrosis to encompass diverse regulated pathways including necroptosis, autophagy, ferroptosis, and pyroptosis. Necroptosis, a caspase-independent inflammatory form of programmed cell death, has emerged as a critical driver of the pathogenesis of cardiovascular disorders, neurodegenerative diseases, and cancer. Concurrently, our understanding of mitochondrial biology has undergone a paradigm shift: mitochondria are no longer viewed merely as bioenergetic powerhouses, but as dynamic signalling hubs that orchestrate metabolic reprogramming, cellular homeostasis, and ultimate cell fate decisions. In this regard, a growing body of evidence suggests that mitochondrial dysfunction is a central rheostat that enables necroptotic execution. This review delineates the mechanistic interplay between necroptosis and mitochondrial dysfunction and systematically analyzes the key molecular mediators and pathological pathways through which mitochondrial dysregulation drives necroptotic activation. Furthermore, this review identifies actionable therapeutic targets and translational strategies for modulating necroptosis in related diseases.