Mitochondrial Quality Control: Insights into Intracerebral Hemorrhage

Abstract

Mitochondrial dysfunction has been identified as a key factor in the pathophysiological changes associated with intracerebral hemorrhage (ICH). As the core of intracellular energy metabolism, mitochondrial homeostasis is highly dependent on the precise regulation of its mitochondrial quality control (MtQC) system. After ICH, dysfunctional mitochondria lead to impaired oxidative phosphorylation and cellular bioenergetic stress, inducing oxidative stress, inflammatory responses, and programmed cell death, further exacerbating cellular damage. To counteract this injury, cells activate a series of MtQC mechanisms for compensatory repair, including mitochondrial dynamics, mitochondrial biogenesis, mitophagy, and intercellular mitochondrial transfer. These stringent mechanisms help maintain the mitochondrial network, restore the integrity of mitochondrial structural and functional integrity, improve neural function, and mitigate brain injury. In this review, we discuss key evidence regarding the role of mitochondrial dysfunction in ICH, focusing on the MtQC mechanisms involved in ICH. We also summarize potential therapeutic strategies targeting MtQC to intervene in ICH, providing valuable insights for clinical applications.

Keywords: Intercellular mitochondrial transfer; Intracerebral hemorrhage; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial quality control; Mitophagy.

Fig. 1

Overview of mitochondrial dysfunction after ICH. Iron overload leads to lipid peroxidation and mitochondrial damage, inducing glutamate production, promoting Ca²⁺ influx, resulting in a decrease in ΔΨm and mitochondrial depolarization. VDAC and MPTP open, leading to the production of mtROS and the release of mtDAMPs and Cytc. These factors further exacerbate oxidative stress, regulate multiple forms of cell death, and amplify inflammatory brain injury through diverse signaling pathways. NMDA: N-methyl-D-aspartate

Fig. 2

Overview of the mechanisms of MtQC in ICH. a Mechanism of mitochondrial dynamics. Under stress conditions, damaged mitochondria initiate fission under the action of DRP1. After fission, mitochondria that cannot restore homeostasis are cleared through mitophagy or apoptosis. Mitochondria can undergo fusion of the OMM and IMM through MFNs and OPA1. b Mechanism of mitochondrial biogenesis. PGC-1α, as the master regulator, once activated through phosphorylation or deacetylation, and it translocates to the nucleus and activates NRF-1/2, enhancing the expression of TFAM, promoting mtDNA replication and transcription, facilitating mitochondrial biogenesis. c Mechanism of mitophagy. Damaged mitochondria can be degraded through PINK1/Parkin-dependent or receptor-mediated pathways. Activated PINK1 recruits Parkin to phosphorylate OMM proteins, which are then recognized by p62, binding to LC3 to target autophagosomes and initiate mitophagy process. NIX, BNIP3, and FUNDC1 bind to LC3 through LIR motifs, while Cardiolipin binds to LC3 via PLSCR3. d Mechanism of intercellular mitochondrial transfer. In the case of injury, recipient cells can obtain healthy mitochondria from donor cells, thereby improving their energy metabolism and promoting cell repair and regeneration, mainly through two pathways: TNTs and EVs. FIS1: Fission 1; MFF: Mitochondrial fission factor; MID49: Mitochondrial dynamics proteins of 49 kDa; MID51: Mitochondrial dynamics proteins of 51 kDa