Endosomal lipid signaling reshapes the endoplasmic reticulum to control mitochondrial function.

Abstract

Cells respond to fluctuating nutrient supply by adaptive changes in organelle dynamics and in metabolism. How such changes are orchestrated on a cell-wide scale is unknown. We show that endosomal signaling lipid turnover by MTM1, a phosphatidylinositol 3-phosphate [PI(3)P] 3-phosphatase mutated in X-linked centronuclear myopathy in humans, controls mitochondrial morphology and function by reshaping the endoplasmic reticulum (ER). Starvation-induced endosomal recruitment of MTM1 impairs PI(3)P-dependent contact formation between tubular ER membranes and early endosomes, resulting in the conversion of ER tubules into sheets, the inhibition of mitochondrial fission, and sustained oxidative metabolism. Our results unravel an important role for early endosomal lipid signaling in controlling ER shape and, thereby, mitochondrial form and function to enable cells to adapt to fluctuating nutrient environments.

• Authors: Wonyul Jang, Dmytro Puchkov, Paula Samsó, YongTian Liang, Michal Nadler-Holly, Stephan J Sigrist, Ulrich Kintscher, Fan Liu, Kamel Mamchaoui, Vincent Mouly, Volker Haucke
• Journal: Science (New York, N.Y.) (Science) Vol. 378 Issue 6625 Pg. eabq5209 (12 16 2022) ISSN: 1095-9203 [Electronic] United States
• PMID: 36520888 (Publication Type: Journal Article)

Chemical References

• phosphatidylinositol 3-phosphate
• Phosphatidylinositol Phosphates
• Phosphatidylinositols
• myotubularin
• Protein Tyrosine Phosphatases, Non-Receptor

Topics

• Humans
• Endoplasmic Reticulum (metabolism)
• Endosomes (metabolism)
• Mitochondria (metabolism)
• Phosphatidylinositol Phosphates (metabolism)
• Phosphatidylinositols (metabolism)
• Signal Transduction
• Protein Tyrosine Phosphatases, Non-Receptor (genetics, metabolism)
• Mitochondrial Dynamics