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Review
. 2025 Apr 17;85(8):1487-1508.
doi: 10.1016/j.molcel.2025.03.003.

Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis

Brandon Chen  1 , Costas A Lyssiotis  2 , Yatrik M Shah  3
Affiliations
Review

Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis

Brandon Chen et al. Mol Cell. .

Abstract

Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is achieved through inter-organellar communication, involving the exchange of metabolites, lipids, and signaling molecules. The functional diversity of metabolite exchange and pathway interactions is enabled by compartmentalization within organelle membranes. Membrane contact sites (MCSs) are critical for facilitating mitochondria-organelle communication, creating specialized microdomains that enhance the efficiency of metabolite and lipid exchange. MCS dynamics, regulated by tethering proteins, adapt to changing cellular conditions. Dysregulation of mitochondrial-organelle interactions at MCSs is increasingly recognized as a contributing factor in the pathogenesis of multiple diseases. Emerging technologies, such as advanced microscopy, biosensors, chemical-biology tools, and functional genomics, are revolutionizing our understanding of inter-organellar communication. These approaches provide novel insights into the role of these interactions in both normal cellular physiology and disease states. This review will highlight the roles of metabolite transporters, lipid-transfer proteins, and mitochondria-organelle interfaces in the coordination of metabolism and transport.

Keywords: endoplasmic reticulum; inter-organellar communication; mitochondria; organellar metabolism; organelle membrane contact sites.

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Conflict of interest statement

Declaration of interests In the past three years, C.A.L. has consulted for Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures, and T-Knife Therapeutics and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-ME1 pathway as a therapeutic approach (US Patent no. 2015126580-A1, 05/07/2015; US Patent no. 20190136238, 05/09/2019; International Patent no. WO2013177426-A2, 04/23/2015).

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