Mitophagy coordinates organelle crosstalk in health and diseases

Eukaryotic cells contain various membrane- and non-membrane-bound organelles, whose spatial and functional organization underpins intracellular homeostasis. Organelle coordination is governed by complex signaling and metabolic networks, often facilitated by direct physical contacts and molecular exchange. Mitochondria, as central hubs of bioenergetic and metabolic activity, are essential to functional coordination among cellular organelles. They engage in diverse cellular processes, encompassing ATP production, biosynthesis of key metabolites, calcium ion buffering, redox balance, and cellular turnover. To preserve their integrity and functionality, dysfunctional mitochondria undergo selective elimination via mitophagy, a specialized form of macroautophagy. Mitophagy plays dual roles in maintaining mitochondrial fidelity and actively shapes interorganelle communication. Through bidirectional signaling, mitophagy influences the activity of multiple organelles, including the endoplasmic reticulum, nucleus, lysosomes, peroxisomes, and lipid droplets. This interorganelle crosstalk is essential for adapting to metabolic stress, maintaining redox balance, and coordinating cell fate decisions. In this review, we explore the intricate signaling networks connecting mitophagy with various organelles and discuss how these interactions influence organ function and overall cellular health. We also highlight emerging small-molecule modulators of mitophagy, providing insight into potential therapeutic strategies aimed at restoring or enhancing organelle communication in pathological conditions.