Figure 1.

Mitochondrial quality control defects mediated by TDP-43 dysregulation.

TDP-43 impairs biogenesis of mitochondrial proteins by altering nuclear-encoded or mitochondria-transcribed mRNA, or by preventing protein import to mitochondrial matrix through TOM/TIM translocases. In particular, TDP-43 perturbs the expression and assembly of complex I subunits leading to mitochondrial dysfunction, as well as mitofusin which causes excessive fragmentation of mitochondria. Mitofusin downregulation may also affect mitochondrial transport and mitophagy. TDP-43 disturbs ER-mitochondria contacts as well by blocking the interaction between VAPB and PTPIP51, and probably between both organelle's mitofusins. ΔΨm: mitochondrial membrane potential; ER: endoplasmic reticulum; mt: mitochondrial; PINK1: PTEN-induced kinase 1; PTPIP51: protein tyrosine phosphatase interacting protein 51; TDP-43: TAR DNA-binding protein of 43 kDa; TIM: translocase of the inner membrane; TOM: translocase of the outer membrane; Ub: ubiquitin; VAPB: vesicle-associated membrane protein-associated protein B.