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Review
. 2021 Nov:150:105192.
doi: 10.1016/j.neuint.2021.105192. Epub 2021 Sep 22.

Rescuing mitochondria in traumatic brain injury and intracerebral hemorrhages - A potential therapeutic approach

Meenakshi Ahluwalia  1 , Manish Kumar  2 , Pankaj Ahluwalia  3 , Scott Rahimi  2 , John R Vender  2 , Raghavan P Raju  4 , David C Hess  5 , Babak Baban  6 , Fernando L Vale  2 , Krishnan M Dhandapani  2 , Kumar Vaibhav  7
Affiliations
Review

Rescuing mitochondria in traumatic brain injury and intracerebral hemorrhages - A potential therapeutic approach

Meenakshi Ahluwalia et al. Neurochem Int. 2021 Nov.

Abstract

Mitochondria are dynamic organelles responsible for cellular energy production. Besides, regulating energy homeostasis, mitochondria are responsible for calcium homeostasis, signal transmission, and the fate of cellular survival in case of injury and pathologies. Accumulating reports have suggested multiple roles of mitochondria in neuropathologies, neurodegeneration, and immune activation under physiological and pathological conditions. Mitochondrial dysfunction, which occurs at the initial phase of brain injury, involves oxidative stress, inflammation, deficits in mitochondrial bioenergetics, biogenesis, transport, and autophagy. Thus, development of targeted therapeutics to protect mitochondria may improve functional outcomes following traumatic brain injury (TBI) and intracerebral hemorrhages (ICH). In this review, we summarize mitochondrial dysfunction related to TBI and ICH, including the mechanisms involved, and discuss therapeutic approaches with special emphasis on past and current clinical trials.

Keywords: Brain injury; Immune activation; Mitochondrial bioenergetics; Mitochondrial biogenesis; Mitophagy; Therapeutic approach.

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Conflict of interest statement

Conflicts of Interest

Authors declare no financial or competing conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Fig. 1
Fig. 1. Mitochondrial injury-mediated pathways of cellular damage in TBI and ICH
Mitochondria is a cellular powerhouse and is critical for cellular survival. However, because of their exposure to oxidant and active cellular respiration, mitochondria are vulnerable to injury (TBI and ICH)-induced stress. In this schematic diagram, we elucidated mitochondrial pathways of injury-induced cellular dysfunction. The main pathways leading to mitochondria-associated cellular dysfunction include: (1) Calcium overload causes mtPTP opening and increased mitochondrial membrane permeability. As a result of aggravated injury-mediated signaling, mitochondria go into overproduction of ROS and loss of ATP. (2) Injury-induced defects in mitochondrial biogenesis (fission and fusion) affects mitochondrial longevity. (3) Impaired intercellular transport leads to reduced number of mitochondria in affected cells. (4) When mitochondria become dysfunctional and pose a threat to cellular integrity, affected cell tries to remove mitochondria through mitophagy. 5) Finally, when survival attempts fade, the affected cell undergoes into cyt c-mediated apoptosis. Increased membrane permeability leads to cytochrome c release and activation of apoptosis. ATP, adenosine triphosphate; cyt c, cytochrome c; Drp1, dynamin-related protein 1; Mfn, mitofusin; mPTP, mitochondrial permeability transition pore; OPA, optic atrophy; ROS, reactive oxygen species; Ca2+, calcium ion.
Fig. 2
Fig. 2. Current treatment strategies for mitochondrial therapeutics in TBI and ICH
Mitochondrial rescue in case of brain injury can be achieved by using drugs that targets: (1) Mitochondrial homeostatic pathways such as mitochondrial biogenesis, and (2) Mitochondrial functional pathways such as mitochondrial bioenergetics including tri-carboxylic acid (TCA) cycle and electron transport chain (ETC), mitochondrial permeability & Ca2+ signaling, specific mitochondrial receptor and anti-oxidative defense mechanism. 7,8-DHF, 7,8-dihydroxyflavone; FCCP: Trifluoromethoxy carbonylcyanide phenylhydrazone; 2,4-DNP: 2, 4-dinitrophenol; NIM811, N-methyl-4-isoleucine-cyclosporine; NAC/NACA: N-acetylcysteine (NAC); N-acetylcysteine amide (NACA).
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