Sam, P. | bioRxiv Science

bioRxiv2020

Impaired phosphatidylethanolamine metabolism activates a reversible stress response that detects and resolves mutant mitochondrial precursors

Phosphatidylethanolamine made in mitochondria has long been recognized as an important precursor for phosphatidylcholine production that occurs in the endoplasmic reticulum (ER). Recently, the strict mitochondrial localization of the enzyme that makes PE in the mitochondrion, phosphatidylserine decarboxylase 1 (Psd1), was questioned. Since a dual localization of Psd1 to the ER would have far-reaching implications, we initiated our study to independently re-assess the subcellular distribution of Psd1. Our results support the unavoidable conclusion that the vast majority, if not all, of functional Psd1 resides in the mitochondrion. Through our efforts, we discovered that mutant forms of Psd1 that impair a self-processing step needed for it to become functional are dually localized to the ER when expressed in a PE-limiting environment. We conclude that severely impaired cellular PE metabolism provokes an ER-assisted adaptive response that is capable of identifying and resolving nonfunctional mitochondrial precursors.

cell biology↗

bioRxiv2018

PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts and white matter changes

Exome sequencing of two sisters with congenital cataracts, short stature and white matter changes identified compound heterozygous variants in the PISD gene, encoding the phosphatidylserine decarboxylase enzyme that converts phosphatidylserine (PS) to phosphatidylethanolamine (PE) in the inner mitochondrial membrane (IMM). Decreased conversion of PS to PE, and depletion of total cellular PE levels in patient fibroblasts are consistent with impaired PISD enzyme activity. Meanwhile, as evidence for mitochondrial dysfunction, patient fibroblasts exhibited more fragmented mitochondrial networks, enlarged lysosomes, decreased maximal oxygen consumption rates and increased sensitivity to 2-deoxyglucose. Moreover, treatment with lyso-PE, which can replenish the mitochondrial pool of PE, restored mitochondrial and lysosome morphology in patient fibroblasts. Functional characterization of the PISD mutations demonstrates that the maternal variant causes an alternative splice product. Meanwhile, the paternal variant impairs autocatalytic self-processing of the PISD protein required for its activity. Finally, evidence for impaired activity of mitochondrial IMM proteases explains why the phenotypes of these PISD patients resemble recently described \"mitochondrial chaperonopathies\". Collectively, these findings demonstrate that PISD is a novel mitochondrial disease gene.

molecular biology↗