FIGURE 5.

Potential mechanisms of DCMA mitochondrial dysfunction. (A) Under physiological conditions, DNAJC19 is targeted to TIM17B by MAGMAS and associates with components of the TIM23 translocation machinery, forming translocase B. DNAJC19 is homologous to yeast Pam18p which stimulates the mtHsp70 activity of the PAM (presequence-associated motor) complex and stabilizes binding of incoming precursors. Moreover, DNAJC19 also interacts with prohibitin-2 (PHB) of the PHB complexes. PHB1/PHB2 oligomers form ring-like complexes that are modeled to delineate specialized membrane domains. Functional segregation of CL and TAZ in such domains may confer acyl chain specificity to TAZ, allowing it to perform physiologically relevant CL remodeling (green). Thus, DNAJC19 may participate in both mitochondrial presequence protein import as well as formation of membrane domains that are important for TAZ-based CL remodeling. (B) In the absence of DNAJC19, the ability of the TIM23 machinery to import proteins across the IMM may be compromised. Consequently, the biogenesis of mitochondrial proteins, such as subunits of respiratory complexes, may be reduced. (C) Further, loss of DNAJC19 prevents the PHB complex-based generation of privileged membrane domains. In the absence of such domains, TAZ remodeling, which may still occur, lacks specificity (red). For clarity, not all components of the TOM, TIM, and PAM complexes are depicted.