Work characterizing a PINK1-IMMT (or PINK1-MIC60) pathway required for mitochondrial functions and neuronal integrity has been pursued in both Drosophila and human. Since mutations in PINK1 are known to cause an early onset form of Parkinson disease, a screen for IMMT coding mutations was undertaken, comparing Parkinson disease patients and controls. Several rare heterozygous variants were identified as potentially implicated in development of the disease. IMMT encodes MIC60, a component of the MICOS complex, a large protein complex of the mitochondrial inner membrane; the IMMT/MIC60 protein plays a role in the maintenance of the MICOS complex stability and the regulation of mitochondrial cristae morphology. There is a single orthologous gene in Drosophila, Mitofilin, for which an amorphic gene trap allele, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
UAS constructs of the human Hsap\IMMT gene have been introduced into flies, including wild-type and the postulated disease-implicated variants. Variant(s) implicated in human disease tested (as transgenic human gene, IMMT): the A4V, T11A, C17F, and R25H variant forms have been introduced into flies; a variant found in healthy controls (R31C) has also been characterized. Expression of the wild-type human gene and each variant was tested in animals heterozygous for a null mutation in the fly Mitofilin gene. Expression of the A4V, T11A, or C17F variants, but not of wild-type Hsap\IMMT or of the R31C variant found in healthy controls, led to severe adult lethality and significantly impaired the larval crawling ability. Expression of the R25H variant, found in one PD patient, compromised the larval crawling ability, but not adult viability. In the more extreme mutations, impaired mitochondrial crista junction formation causing 'onion-like' mitochondria in late third instar larval body wall muscles were observed; mitochondrial localization of both the mutant human protein and the endogenous Mitofilin protein was greatly reduced.
Animals homozygous for an amorphic allele of Dmel\Mitofilin typically die during the pupal stage; third instar larvae display a significant impairment in crawling ability and their body wall muscles display abnormal 'onion-like' mitochondria, in which crista membranes form multiple concentric layers and crista junctions are lacking. Physical and genetic interactions (including with Dmel\Pink1) have been described for Dmel\Mitofilin; see below and in the Mitofilin gene report.
[updated Jan 2020 by FlyBase; FBrf0222196]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from MIM:168600; 2013.07.23]
Parkinson disease is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 may be referred to as juvenile-onset disease. [from Genetics Home Reference, GHR_condition:parkinson-disease, 2015.02.13]
IMMT encodes a component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane. IMMT plays an important role in the maintenance of the MICOS complex stability and the regulation of mitochondrial cristae morphology. [Gene Cards, IMMT; 2020.01.15]
One to one: 1 human to 1 Drosophila
High-scoring ortholog of human IMMT (1 Drosophila to 1 human). Dmel\Mitofilin shares 27% identity and 44% similarity with the human gene.
