Targeting mitochondrial fitness for cardioprotection

Graphical AbstractProlonged myocardial ischemia leads to mitochondrial damage, resulting in loss of membrane potential (m delta psi) and reduced hydrolysis of PINK1. As PINK1 accumulates on the outer mitochondrial membrane (OMM), it phosphorylates Parkin at Ser65 which triggers the translocation of Parkin from the cytoplasm to the surface of the damaged mitochondria, where it ubiquitinates several outer mitochondrial membrane proteins. The ubiquitinated mitochondria are recognised by autophagosomes through receptors like p62, initiating their degradation. Treatment with a single bolus of PR-364, administered 2 hours after PCAL, enhanced mitophagy through Parkin activation and promoted mitochondrial biogenesis via PGC-1α during prolonged ischaemia and limited post-infarction adverse left ventricle remodelling. Parkin-independent pathways of mitophagy which have been targeted for cardioprotection include BNIP3 and Rab9. PCAL, permanent coronary artery ligation; PINK1, PTEN-induced putative kinase protein-1; BNIP3, Bcl2 interacting protein 3; FUNDC1, FUN14 domain-containing 1; PGC-1a, peroxisome proliferator-activated receptor gamma co-activator 1 alpha; AMPK, AMP activated protein kinase; Drp1, dynamin-related protein 1; Ulk1, autophagy-related protein-1 homolog UNC-51-like kinase 1; Rip1, receptor-interacting protein; LC3, microtube-associated proteins; S, serine.Open in new tabDownload slide