Abstract
The human nuclear and mitochondrial genomes co-exist within each cell. While the mitochondrial genome encodes for a limited number of proteins, transfer RNAs, and ribosomal RNAs, the vast majority of mitochondrial proteins are encoded in the nuclear genome. Of the multitude of mitochondrial disorders known to date, only a fifth are maternally inherited. The recent characterization of the mitochondrial proteome therefore serves as an important step toward delineating the nosology of a large spectrum of phenotypically heterogeneous diseases. Following the identification of the first nuclear gene defect to underlie a mitochondrial disorder, a plenitude of genetic variants that provoke mitochondrial pathophysiology have been molecularly elucidated and classified into six categories that impact: (1) oxidative phosphorylation (subunits and assembly factors); (2) mitochondrial DNA maintenance and expression; (3) mitochondrial protein import and assembly; (4) mitochondrial quality control (chaperones and proteases); (5) iron–sulfur cluster homeostasis; and (6) mitochondrial dynamics (fission and fusion). Here, we propose that an additional class of genetic variant be included in the classification schema to acknowledge the role of genetic defects in phospholipid biosynthesis, remodeling, and metabolism in mitochondrial pathophysiology. This seventh class includes a small but notable group of nuclear-encoded proteins whose dysfunction impacts normal mitochondrial phospholipid metabolism. The resulting human disorders present with a diverse array of pathologic consequences that reflect the variety of functions that phospholipids have in mitochondria and highlight the important role of proper membrane homeostasis in mitochondrial biology.
Highlights
The human nuclear and mitochondrial genomes co-exist within each cell
The organelle is the home for the tricarboxylic acid cycle, fatty acid beta-oxidation, iron– sulfur cluster biogenesis, a portion of the urea cycle, and steps in the porphyrin and pyrimidine biosynthetic pathways
The mitochondrion directly contributes to cellular phospholipid metabolism by hosting machinery that can produce at least four distinct phospholipids: phosphatidic acid (PA), phosphatidylglycerol (PG), cardiolipin (CL), and phosphatidylethanolamine (PE)
Summary
The human nuclear and mitochondrial genomes co-exist within each cell. While the mitochondrial genome encodes for a limited number of proteins, transfer RNAs, and ribosomal RNAs, the vast majority of mitochondrial proteins are encoded in the nuclear genome. Other mechanisms that are hypothesized to play a role in the TAZ-based establishment of CL molecular species include the specificity of enzymes immediately upstream of TAZ that initiate the remodeling process and dictate which substrates are available to TAZ (Baile et al, 2014b), as well as the dietary intake of fatty acids (Stavrovskaya et al, 2013).
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