Two unrelated patients with suspected mitochondrial disease were each found to carry homozygous missense variants in ATP5F1D: in the more severe case, P82L, and in the less severe case, V106G. ATP5F1D is a nuclear gene that encodes the delta subunit of the mitochondrial ATP synthase complex (complex V). There is a single orthologous gene in Drosophila, ATPsynδ, for which RNAi constructs and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\ATP5F1D gene have been introduced into flies, including wild-type and variants implicated in disease. Heterologous rescue (functional complementation) is observed: the lethality observed for pan-neuronal knockdown of Dmel\ATPsynδ is rescued by expression of wild-type Hsap\ATP5F1D, but not by expression of either of the two disease-associated variants. A knockdown phenotype effected by an eye-specific driver shows partial rescue by the disease-implicated variants; in this system, the V106G variant exhibits the least rescue and thus acts like the more severely affected of the two variants. Variant(s) implicated in human disease tested (as transgenic human gene, ATP5F1D): the P82L and V106G variant forms have been introduced into flies; both of these amino acids are very highly conserved.
Ubiquitous or pan-neuronal knockdown of Dmel\ATPsynδ, effected by RNAi, results in lethality early in development. A large number of physical interactions for Dmel\ATPsynδ have been described; see below and in the ATPsynδ gene report.
[updated Jul. 2018 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]
[MITOCHONDRIAL COMPLEX V (ATP SYNTHASE) DEFICIENCY, NUCLEAR TYPE 5; MC5DN5](https://omim.org/entry/618120)
[ATP SYNTHASE F1, SUBUNIT DELTA; ATP5F1D](https://omim.org/entry/603150)
Described in 2 patients; both exhibited mild developmental delay and other symptoms. Both suffered recurrent episodic metabolic decompensation associated with lactic acidosis, muscle breakdown, and increased serum creatine kinase (in the first case) or with lethargy, seizures, lactic acidosis, ketoacidosis, and hyperammonemia (in the second case). One patient developed dilated cardiomyopathy; the other had no cardiac abnormalities. (Olahova et al., 2018; pubmed:29478781) [from MIM:618120; 2019.03.14]
Mitochondrial complex V (ATP synthase) deficiency nuclear type 5 (MC5DN5) is caused by homozygous mutation in the ATP5F1D gene.
Mitochondria derived from 1 patient's cells showed a decrease in the number of cristae and impaired maximal respiration in response to palmitate compared to controls. Plasma analysis of metabolites and lipids in this 1 patient was consistent with impaired mitochondrial fatty acid oxidation and accumulation of citric acid cycle intermediates. (Olahova et al., 2018; pubmed:29478781) [from MIM:618120; 2019.03.14]
Mitochondrial complex V (ATP synthase) effects the final step of oxidative phosphorylation in the mitochondrial respiratory chain. The ATP5F1D gene (previously ATP5D) encodes the delta subunit of the mitochondrial ATP synthase complex.
One to one: 1 human to 1 Drosophila
High-scoring ortholog of human ATP5F1D (1 Drosophila to 1 human). Dmel\ATPsynδ shares 48% identity and 66% similarity with the human gene.
