Mitochondrial PE potentiates respiratory enzymes to amplify skeletal muscle aerobic capacity

Abstract

Exercise capacity is a strong predictor of all-cause mortality. Skeletal muscle mitochondrial respiratory capacity, its biggest contributor, adapts robustly to changes in energy demands induced by contractile activity. While transcriptional regulation of mitochondrial enzymes has been extensively studied, there is limited information on how mitochondrial membrane lipids are regulated. Here, we show that exercise training or muscle disuse alters mitochondrial membrane phospholipids including phosphatidylethanolamine (PE). Addition of PE promoted, whereas removal of PE diminished, mitochondrial respiratory capacity. Unexpectedly, skeletal muscle–specific inhibition of mitochondria-autonomous synthesis of PE caused respiratory failure because of metabolic insults in the diaphragm muscle. While mitochondrial PE deficiency coincided with increased oxidative stress, neutralization of the latter did not rescue lethality. These findings highlight the previously underappreciated role of mitochondrial membrane phospholipids in dynamically controlling skeletal muscle energetics and function.

IGF2 deficiency causes mitochondrial defects in skeletal muscle

“…This exercise-induced adaptation resulted in positive alternations in mitochondrial function [14]. As for mitochondrial function, exercise promoted ROS loss and high mitochondrial membrane potential, leading to increased respiration function [15]. Apart from that, remodeling of mitochondrial network (fusion and fission) from exercise can also be observed to improve mitochondria's efficiency [16].…”

Adaptive optimization of the OXPHOS assembly line partially compensates lrpprc-dependent mitochondrial translation defects in mice

“…Further studies in which upregulation of CLs is prevented in liver-specific Lrpprc -deficient mice will be required to confirm that changes in the lipid milieu underlie the stabilization of CIV. Interestingly, recent evidence indicates that greater mitochondrial PE could also potentiate respiratory enzymes activity 65 . Our lipidomic analysis pointing to a relative increase of PE species, compared to PC species, supports the notion that GPL remodeling may be a mechanism to preserve or potentiate the activity of the residual CIV in H- Lrpprc −/− mice.…”

Phospholipid ebb and flow makes mitochondria go

“…Genetic ablation of PISD in mouse is embryonically lethal, highlighting the importance of the mitochondrial pathway that cannot be compensated for by extramitochondrial PE pools ( Steenbergen et al, 2005 ). PE is crucial for mitochondrial functionality, as demonstrated by OXPHOS defects in the absence of Psd1/PISD and its role in the regulation of mitochondrial dynamics and biogenesis of OMM proteins ( Becker et al, 2013 ; Birner et al, 2001 ; Böttinger et al, 2012 ; Calzada et al, 2019 ; Heden et al, 2019 ; Tasseva et al, 2013 ).…”