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Figure 1 | BMC Biology

Figure 1

From: Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection

Figure 1

Mitochondrial protein import and PINK1-mediated mitophagy. (A) The vast majority of mitochondrial proteins are encoded by nuclear genes, synthesized on cytosolic ribosomes and targeted to mitochondria via mitochondrial targeting sequences (MTS). To reach the mitochondrial matrix, proteins synthesized on cytosolic ribosomes first interact with the translocase of the outer membrane (TOM) and then with the translocase of the inner membrane (TIM). Crossing the inner membrane requires both complexes, a membrane potential (Ψ) across the inner mitochondrial membrane that is generated by the respiratory chain, ATP and molecular chaperones (CH) within the mitochondrial matrix. Once in the matrix, the MTS is typically cleaved, allowing the protein to fold and assemble appropriately. Perturbations to the TOM/TIM complexes, respiratory chain, membrane potential and mitochondrial chaperones results in reduced mitochondrial import efficiency. (B) The kinase PINK1 serves to monitor mitochondrial health and initiate mitochondrial degradation when an organelle is severely damaged. Normally, PINK1, localized to mitochondria by its MTS sequence, is efficiently imported into the mitochondrion and subsequently degraded. However, when a mitochondrion is damaged (red), resulting in a depleted inner membrane potential or because of high levels of unfolded proteins in the matrix, PINK1 fails to be imported and accumulates on the mitochondrial outer membrane, allowing recognition of the damaged organelle in a sequence of steps, the first of which is the recruitment of the ubiquitin ligase Parkin to the outer mitochondrial membrane. PINK1 phosphorylates ubiquitin (Ub) and the ubiquitin ligase Parkin, and activated Parkin then ubiquitinates outer mitochondrial membrane proteins, leading to the recruitment of the autophagosome machinery and engulfment of the damaged organelle. Precise engulfment requires the Rab GAP TBC1D15 (shown in grey), which is bound to the mitochondrial outer membrane via interaction with LC3/GABARAP (not shown). The autophagosome then fuses with a lysosome, leading to degradation of the defective mitochondria by the proteases and lipases that reside in lysosomes.

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