Serum starvation induces anti-apoptotic cIAP1 to promote mitophagy through ubiquitination.
Mitophagy is a highly specialised type of autophagy that plays an important role in regulating mitochondrial dynamics and controls cellular quality during stress. In this study, we established that serum starvation led to induction of cellular inhibitor of apoptosis protein-1 (cIAP1), which regulates mitophagy through ubiquitination. Importantly, gain and loss of function of cIAP1 resulted in concomitant alteration in mitophagy confirming the direct implication of cIAP1 in induction of mitophagy. Interestingly, it was observed that cIAP1 translocated to mitochondria to associate with TOM20, Ulk1, and LC3 to initiate mitophagy. Further, cIAP1-induced mitophagy led to dysfunctional mitochondria that resulted in abrogation of mitochondrial oxygen consumption rate along with the decrease in ATP levels. The ubiquitination of cIAP1 was found to be the critical regulator of mitophagy. The disruption of cIAP1-ubiquitin interaction by PYR41 ensured the abrogation of cIAP1-LC3 interaction and mitophagy inhibition. Our study revealed an important function of cIAP1 as a crucial molecular link between autophagy and apoptosis for regulation of mitochondrial dynamics to mitigate cellular stress.
Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
Subhadip
S
Mukhopadhyay
Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
Prajna Paramita
PP
Naik
Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
Prashanta Kumar
PK
Panda
Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
Niharika
N
Sinha
Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
Durgesh Nandini
DN
Das
Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India. Electronic address: sbhutia@nitrkl.ac.in.
Sujit Kumar
SK
Bhutia
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001693:Biological Transport, Active; D016895:Culture Media, Serum-Free; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000502:physiology; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D063306:Mitophagy / Q000502:physiology*; D010101:Oxygen Consumption; D011956:Receptors, Cell Surface / Q000378:metabolism; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D016895:Culture Media, Serum-Free; D051034:Inhibitor of Apoptosis Proteins; C477012:MAP1LC3A protein, human; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011956:Receptors, Cell Surface; C084008:TOMM20 protein, human; D000255:Adenosine Triphosphate; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases
Apoptosis; Mitochondria; Mitophagy; Serum starvation; Ubiquitination; cIAP1