TECPR2 Maintains Mitochondrial Homeostasis by Selective Targeting Mito-Autophagosomes to Lysosomes

Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare neurological disease linked to several mutations in the coding sequence of human TECPR2 encoding for Tectonin β-propeller repeat containing protein 2 (TECPR2). This autosomal recessive disease is characterized by developmental delay, intellectual disability, severe autonomic and sensory dysfunction as well as hypotonia and unexplained fractures. We have previously implicated TECPR2, a multi-domain protein comprised of three β-propellers and a large intrinsic denatured region in autophagy. In current study we provide new evidence for a key role for TECPR2 in mitophagy. We utilize primary fibroblast cells derived from HSAN9 patients and MEF cells isolated from TECPR2 knockout mice to show that lack of TECPR2 leads to mitochondrial dysfunction. Our findings indicate that mitochondrial failure results in impaired clearance of aberrant mitochondria, a process mediated by selective autophagy termed mitophagy. We show that loss of TECPR2 leads to inhibition of Parkin-dependent mitophagy. Our working hypothesis implies that TECPR2 couples between autophagosome completion and recruitment of damaged mitochondria into autophagosome to maintain mitochondrial homeostasis.