PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy.
Mitochondrial fission is essential for the degradation of damaged mitochondria. It is currently unknown how the dynamin-related protein 1 (DRP1)-associated fission machinery is selectively targeted to segregate damaged mitochondria. We show that PTEN-induced putative kinase (PINK1) serves as a pro-fission signal, independently of Parkin. Normally, the scaffold protein AKAP1 recruits protein kinase A (PKA) to the outer mitochondrial membrane to phospho-inhibit DRP1. We reveal that after damage, PINK1 triggers PKA displacement from A-kinase anchoring protein 1. By ejecting PKA, PINK1 ensures the requisite fission of damaged mitochondria for organelle degradation. We propose that PINK1 functions as a master mitophagy regulator by activating Parkin and DRP1 in response to damage. We confirm that PINK1 mutations causing Parkinson disease interfere with the orchestration of selective fission and mitophagy by PINK1.
Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, England, UK k.pryde@ucl.ac.uk.
Kenneth R
KR
Pryde
Faculty of Brain Sciences, University College London, London W1T 7NF, England, UK.
Heather L
HL
Smith
Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, England, UK.
Kai-Yin
KY
Chau
Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, England, UK.
Anthony H V
AH
Schapira
D002118:Calcium / Q000737:chemistry / Q000502:physiology; D002460:Cell Line; D020868:Gene Silencing; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000502:physiology*; D063306:Mitophagy / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
D002118:Calcium; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein