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J Neurosci. 2019 Mar 6;39(10):1930-1943. doi: 10.1523/JNEUROSCI.3415-17.2018. Epub 2019 Jan 9.

Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury.

Chao H1,2,3, Lin C1, Zuo Q4, Liu Y1, Xiao M5,6,7, Xu X1, Li Z1, Bao Z1, Chen H8,9, You Y1, Kochanek PM3, Yin H5,6,7,10, Liu N1, Kagan VE2,11, Bayır H12,3,13, Ji J14,2,3.

Author information

1
Departments of Neurosurgery and.
2
Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health.
3
Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
4
Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
5
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai 200031, China.
6
University of the Chinese Academy of Sciences, CAS, Beijing 100049, China.
7
School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.
8
Department of Medical Genetics, Nanjing University School of Medicine, Nanjing 210093, China.
9
Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210029, China.
10
Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100022, China.
11
Laboratory of Navigational Redox Lipidomics and Department of Human Pathology, IM Sechenov Moscow State Medical University, Moscow 119991, Russian Federation, and.
12
Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, bayihx@ccm.upmc.edu jijing@njmu.edu.cn.
13
Children's Neuroscience Institute, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224.
14
Departments of Neurosurgery and bayihx@ccm.upmc.edu jijing@njmu.edu.cn.

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.

KEYWORDS:

apoptosis; autophagy; cardiolipin; mitophagy; neuroprotection; phospholipid

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