This report describes a model of mitochondrial complex V (ATP synthase) deficiency (MC5D) using mutations of the Drosophila gene ATPsynC. Mitochondrial complex V carries out the final step of oxidative phosphorylation in the mitochondrial respiratory chain; impairment results in severe neuromuscular disease. Thus far, at least 6 of the 17 nuclear-encoded components of the complex in human have been implicated in disease (see MIM:PS604273). Dmel\ATPsynC is orthologous to 3 paralogs in human, ATP5MC1, ATP5MC2, and ATP5MC3; to date, none of the human ATP5MC genes has been associated with MC5D.
Two of the human genes, Hsap\ATP5MC2 and Hsap\ATP5MC3, have been introduced into flies, but have not been characterized. ATP5MC1 has not been introduced into flies.
A range of mutations has been created in Dmel\ATPsynC, including missense mutations and mutations affecting level of expression. Animals homozygous for loss-of-function mutations typically die in the first instar stage. Mutations resulting in reduced levels of expression produce complex pleiotropic phenotypes; in some cases survival to adulthood is observed, but the animals exhibit developmental delay, locomotor defects, and reduced fertility; defects in mitochondrial morphology are observed.
[updated Aug. 2020 by FlyBase; FBrf0222196]
Leigh syndrome may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes, including complex V deficiency.
Mitochondrial complex V deficiency can cause a wide variety of signs and symptoms affecting many organs and systems of the body, particularly the nervous system and the heart. The disorder can be life-threatening in infancy or early childhood. Affected individuals may have feeding problems, slow growth, low muscle tone (hypotonia), extreme fatigue (lethargy), and developmental delay. They tend to develop elevated levels of lactic acid in the blood (lactic acidosis), which can cause nausea, vomiting, weakness, and rapid breathing. High levels of ammonia in the blood (hyperammonemia) can also occur in affected individuals, and in some cases result in abnormal brain function (encephalopathy) and damage to other organs. Other common features are hypertrophic cardiomyopathy and a characteristic pattern of facial features. [from Genetics Home Reference, Mitochondrial complex V deficiency; 2020.08.14]
ATP5MC1, ATP5MC2, and ATP5MC3 encode a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). These three genes encode subunit c of the proton channel. Each of the three genes have distinct mitochondrial import sequences but encode the identical mature protein. [Gene Cards, ATP5MC1, ATP5MC2, ATP5MC3; 2020.08.14]
The precursor polypeptide encoded by ATPsynC is 138 amino acids long and consists of a putative mitochondrial import sequence of 63 residues, which is cleaved off in order to produce a mature, functional protein of 75 amino acids. As for many mitochondrial proteins encoded by nuclear genes, the N-terminal signal peptide shows an opposite degree of evolutionary constraint than the remaining mature portion of the ATP synthase subunit c, which has barely changed throughout metazoan evolution (FBrf0239766).
Many to one: 3 human gene to 1 Drosophila gene.
Many to one: 3 human gene to 1 Drosophila gene.
Many to one: 3 human gene to 1 Drosophila gene.
Moderate- to high-scoring ortholog of human ATP5MC1, ATP5MC2, and ATP5MC3. Dmel\ATPsynC shares 64-71% identity and 76-83% similarity with the human genes.
