Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death.
Opening of the MPT (mitochondrial permeability transition) pore is a critical event in mitochondrial-mediated cell death. However, with the exception of CypD (cyclophilin D), the exact molecular composition of the MPT pore remains uncertain. C1qbp (complement 1q-binding protein) has recently been hypothesized to be an essential component of the MPT pore complex. To investigate whether C1qbp indeed plays a critical role in MPT and cell death, we conducted both gain-of-function and loss-of-function experiments in MEFs (mouse embryonic fibroblasts). We first confirmed that C1qbp is a soluble protein that localizes to the mitochondrial matrix in mouse cells and tissues. Similarly, overexpression of C1qbp in MEFs using an adenovirus resulted in its exclusive localization to mitochondria. To our surprise, increased C1qbp protein levels actually suppressed H2O2-induced MPT and cell death. Antithetically, knockdown of endogenous C1qbp with siRNA (small interfering RNA) sensitized the MEFs to H2O2-induced MPT and cell death. Moreover, we found that C1qbp could directly bind to CypD. Therefore C1qbp appears to act as an endogenous inhibitor of the MPT pore, most likely through binding to CypD, and thus protects cells against oxidative stress.
McGee
Allison M
AM
Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, Missouri, 65211, USA.
Baines
Christopher P
CP
D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D015922:Complement C1q; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D018960:Hyaluronan Receptors / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D051336:Mitochondrial Membranes / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D018384:Oxidative Stress; D021381:Protein Transport; D012995:Solubility
C490193:C1qbp protein, mouse; D000081406:Peptidyl-Prolyl Isomerase F; D018960:Hyaluronan Receptors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; C000631446:PPIF protein, mouse; D015922:Complement C1q; D006861:Hydrogen Peroxide; D021983:Cyclophilins