Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury
- Honglu Chao1,3,4,*,
- Chao Lin1,*,
- Qiang Zuo2,*,
- Yinlong Liu1,
- Mengqing Xiao5,6,7,
- Xiupeng Xu1,
- Zheng Li1,
- Zhongyuan Bao1,
- Huimei Chen8,9,
- Yongping You1,
- Patrick M. Kochanek4,
- Huiyong Yin5,6,7,10,
- Ning Liu1,
- Valerian E. Kagan3,11,
- Hülya Bayır3,4,12, and
- Jing Ji1,3,4
- 1Departments of Neurosurgery and
- 2Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China,
- 3Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health,
- 4Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219,
- 5Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai 200031, China,
- 6University of the Chinese Academy of Sciences, CAS, Beijing 100049, China,
- 7School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China,
- 8Department of Medical Genetics, Nanjing University School of Medicine, Nanjing 210093, China,
- 9Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210029, China,
- 10Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100022, China,
- 11Laboratory of Navigational Redox Lipidomics and Department of Human Pathology, IM Sechenov Moscow State Medical University, Moscow 119991, Russian Federation, and
- 12Children's Neuroscience Institute, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224
-
Author contributions: H. Chao, C.L., Q.Z., V.E.K., H.B., and J.J. wrote the first draft of the paper; H. Chao, C.L., Q.Z., H. Chen, Y.Y., P.M.K., H.Y., N.L., V.E.K., H.B., and J.J. edited the paper; H. Chao, C.L., H. Chen, Y.Y., V.E.K., H.B., and J.J. designed research; H. Chao, C.L., Q.Z., Y.L., M.X., X.X., Z.L., Z.B., and J.J. performed research; H. Chao, C.L., H.Y., V.E.K., and H.B. contributed unpublished reagents/analytic tools; H. Chao, C.L., Q.Z., V.E.K., H.B., and J.J. analyzed data; H. Chao, C.L., Q.Z., P.M.K., H.Y., V.E.K., H.B., and J.J. wrote the paper.
-
↵*H. Chao, C.L., and Q.Z. contributed equally to this work.
Abstract
Mitochondrial energy production is essential for normal brain function. Traumatic brain injury (TBI) increases brain energy demands, results in the activation of mitochondrial respiration, associated with enhanced generation of reactive oxygen species. This chain of events triggers neuronal apoptosis via oxidation of a mitochondria-specific phospholipid, cardiolipin (CL). One pathway through which cells can avoid apoptosis is via elimination of damaged mitochondria by mitophagy. Previously, we showed that externalization of CL to the mitochondrial surface acts as an elimination signal in cells. Whether CL-mediated mitophagy occurs in vivo or its significance in the disease processes are not known. In this study, we showed that TBI leads to increased mitophagy in the human brain, which was also detected using TBI models in male rats. Knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3, responsible for CL translocation to the outer mitochondrial membrane, significantly decreased TBI-induced mitophagy. Inhibition of mitochondrial clearance by 3-methyladenine, mdivi-1, or phospholipid scramblase-3 knockdown after TBI led to a worse outcome, suggesting that mitophagy is beneficial. Together, our findings indicate that TBI-induced mitophagy is an endogenous neuroprotective process that is directed by CL, which marks damaged mitochondria for elimination, thereby limiting neuronal death and behavioral deficits.
SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) increases energy demands leading to activation of mitochondrial respiration associated with enhanced generation of reactive oxygen species and resultant damage to mitochondria. We demonstrate that the complete elimination of irreparably damaged organelles via mitophagy is activated as an early response to TBI. This response includes translocation of mitochondria phospholipid cardiolipin from the inner membrane to the outer membrane where externalized cardiolipin mediates targeted protein light chain 3-mediated autophagy of damaged mitochondria. Our data on targeting phospholipid scramblase and cardiolipin synthase in genetically manipulated cells and animals strongly support the essential role of cardiolipin externalization mechanisms in the endogenous reparative plasticity of injured brain cells. Furthermore, successful execution and completion of mitophagy is beneficial in the context of preservation of cognitive functions after TBI.
- Received November 30, 2017.
- Revision received November 21, 2018.
- Accepted December 28, 2018.
- Copyright © 2019 the authors 0270-6474/19/391931-14$15.00/0
