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.

Label-Free Single-Cell SERS Detection and Fluorescence Imaging of Molecular Responses to Endoplasmic Reticulum Stress under Electrical Stimulation

“…The outer membrane of the mitochondria is associated with the ER membrane, which plays an important role in Ca 2+ conduction . Therefore, the shape and number of mitochondria as dynamic organelles that grow, divide, and fuse were checked using the specific commercial dyes of Mito-Tracker Green during the ES process, whose fluorescence intensity was not influenced by the mitochondrial membrane potential .…”

“…The outer membrane of the mitochondria is associated with the ER membrane, which plays an important role in Ca 2+ conduction. 27 Therefore, the shape and number of mitochondria as dynamic organelles that grow, divide, and fuse were checked using the specific commercial dyes of Mito-Tracker Green during the ES process, whose fluorescence intensity was not influenced by the mitochondrial membrane potential. 11 As shown in Figure 3a,3b, the fluorescence intensity of Mito-Tracker Green within HepG2 cells was gradually reduced on increasing the voltage, indicating a significant decrease in the number of mitochondria.…”

The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after open mitosis in mammalian cells

“…The two types of ER–NE junctions we observed – with and without a luminal connection – raise the possibility that ER–NE junctions can change configuration. The membrane contact sites between the ER and other organelles such as mitochondria, endosome, and plasma membrane respond to various environmental cues including nutrient stress, ER stress and calcium stimulation (Donahue et al, 2022; Jang et al, 2022). Similarly, the membrane junctions between the ER and the NE might change their morphology in response to environmental stimuli.…”

Hibernating ribosomes tether to mitochondria as an adaptive response to cellular stress during glucose depletion

“…In yeast, glucose starvation triggers cellular adaptation by limiting the movement of macromolecular assemblies (6,11). Under these conditions, protein synthesis becomes unfavorable at both the transcriptional and translational levels while proteasomal activity and autophagy are enhanced, leading to adaptive modifications in the endoplasmic reticulum and mitochondria (4,(12)(13)(14)(15). Mitochondrial fragmentation is a common response to nutrient depletion, changes in carbon source and metabolic shifts.…”

“…Cells initiate adaptive responses to counteract cellular stress resulting from nutrient depletion. This is accomplished through a shift in metabolic pathways and through alterations in organellar dynamics ( 1–4 ). In certain instances, cells exit the division cycle and enter a quiescent state, enabling them to endure harsh environmental conditions ( 5 , 6 ).…”