Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

Abstract

Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

“…Mutations in Opa1 cause autosomal-dominant optic atrophy, a disease of progressive blindness due to degeneration of retinal ganglion cells, but which can also include more widespread neuronal degeneration (Alexander et al, 2000; Chen and Chan, 2006; Delettre et al, 2000; McFarland et al, 2010). Truncations of the human milton isoform TRAK1 cause fatal encephalopathy (Barel et al, 2017). As indicated above, the most common mitostatic disease identified to date is Parkinson’s disease.…”

“…Mitofusin2 mutations cause Charcot-Marie-Tooth disease type 2A (Kijima et al, 2005; Zuchner et al, 2004) and Opa1 mutations are responsible for autosomal dominant optic atrophy (Alexander et al, 2000; Delettre et al, 2000; McFarland et al, 2010). Mutations of Drp1, MFN, and Trak1 (Milton) are very rare in humans, but cause early lethality with broad defects that include neurological symptoms such as fetal encephalopathy and optic atrophy (Barel et al, 2017; McFarland et al, 2010). …”

“…Examples would include many mutations in the complexes of the electron transport chain that result in encephalopathies, ataxia, and cerebellar atrophy. True mitostatic disorders, caused by mutations in the proteins that govern mitochondrial dynamics and mitophagy, result in diseases that range from severe developmental abnormalities, to optic atrophy, peripheral neuropathy, and Parkinson’s disease (Barel et al, 2017; Chen and Chan, 2006; Pickrell and Youle, 2015). Disorders that more broadly affect axonal transport, such as tauopathies and SOD1 mutations, may include phenotypes with a significant mitochondrial etiology (De Vos et al, 2008; Millecamps and Julien, 2013).…”

Modulation of alternative splicing of trafficking genes by genome editing reveals functional consequences in muscle biology

“…When the formation of the TRAK1-kinesin adaptor is inhibited in axons of hippocampal pyramidal neurons, mitochondrial mobility is decreased (Brickley and Stephenson, 2011). Furthermore, TRAK1 depletion leads to mitochondrial fragmentation (Lee et al, 2017) and a recent report identified mutations in the TRAK1 gene in individuals with neurodevelopmental delay, seizures, and fatal encephalopathy (Barel et al, 2017). Fibroblasts derived from these individuals exhibit damaged mitochondria distribution due to impaired mitochondrial motility and reduced respiration capacity (Barel et al, 2017).…”

“…Furthermore, TRAK1 depletion leads to mitochondrial fragmentation (Lee et al, 2017) and a recent report identified mutations in the TRAK1 gene in individuals with neurodevelopmental delay, seizures, and fatal encephalopathy (Barel et al, 2017). Fibroblasts derived from these individuals exhibit damaged mitochondria distribution due to impaired mitochondrial motility and reduced respiration capacity (Barel et al, 2017). Still, the function of TRAK1 in cardiac and skeletal muscle tissue has not been described.…”