Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury.

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.

• Authors: Honglu Chao, Chao Lin, Qiang Zuo, Yinlong Liu, Mengqing Xiao, Xiupeng Xu, Zheng Li, Zhongyuan Bao, Huimei Chen, Yongping You, Patrick M Kochanek, Huiyong Yin, Ning Liu, Valerian E Kagan, Hülya Bayır, Jing Ji
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 39 Issue 10 Pg. 1930-1943 (03 06 2019) ISSN: 1529-2401 [Electronic] United States
• PMID: 30626699 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 the authors 0270-6474/19/391931-14$15.00/0.

Chemical References

• Cardiolipins

Topics

• Animals
• Apoptosis (physiology)
• Brain (metabolism, ultrastructure)
• Brain Injuries, Traumatic (metabolism, pathology)
• Cardiolipins (metabolism)
• Humans
• Male
• Mitochondrial Membranes (metabolism)
• Mitophagy (physiology)
• Neurons (metabolism, ultrastructure)
• Rats, Sprague-Dawley
• Signal Transduction