Mitochondrial quality control and transfer communication in neurological disorders and neuroinflammation

Abstract

Mitochondria, as the primary energy factories of cells, play a pivotal role in maintaining nervous system function and regulating inflammatory responses. The balance of mitochondrial quality control is critical for neuronal health, and disruptions in this balance are often implicated in the pathogenesis of various neurological disorders. Mitochondrial dysfunction not only exacerbates energy deficits but also triggers neuroinflammation through the release of damage-associated molecular patterns (DAMPs), such as mitochondrial DNA (mtDNA) and reactive oxygen species (ROS). This review examines the mechanisms and recent advancements in mitochondrial quality control in neurological diseases, focusing on processes such as mitochondrial fusion and fission, mitophagy, biogenesis, and protein expression regulation. It further explores the role of mitochondrial dysfunction and subsequent inflammatory cascades in conditions such as ischemic and hemorrhagic stroke, neurodegenerative diseases and brain tumors. Additionally, emerging research highlights the significance of mitochondrial transfer mechanisms, particularly intercellular transfer between neurons and glial cells, as a potential strategy for mitigating inflammation and promoting cellular repair. This review provides insights into the molecular underpinnings of neuroinflammatory pathologies while underscoring the translational potential of targeting mitochondrial quality control for therapeutic development.

Keywords: mitochondrial; mitochondrial quality control; mitochondrial transfer; neuroinflammation; neurological disorders.

Figure 1

Mitochondrial quality control (e.g., mitochondrial biosynthesis, function and metabolism, mitochondrial fission and fusion as well as mitophagy), and mitochondrial-mediated inflammatory responses. IMM inner mitochondrial membrane, OMM outer mitochondrial membrane, ETC electron transfer chain, ADP adenosine diphosphate, ATP adenosine triphosphate, TCA tricarboxylic acid, ROS reactive oxygen species, mPTP mitochondrial permeability transition pore, ANT adenosine nucleotide translocase, CYPD cyclophilin D, VDAC voltage-dependent anion channel, TAG triacylglycerol, Co A coenzyme A, CPT1/2 carnitine palmitoyl transferase 1/2, CPS1 carbamoyl-phosphate synthase 1, PEP Phosphoenolpyruvate, Cyt C cytochrome C, HSP heat shock protein, NLRP3 NOD-like receptor protein3, GPX4 glutathione peroxidase 4, VCP valosin containing protein, CLPXP caseinolytic protease X and protease P complex, LONP1 lon peptidase 1, mtDNA mitochondrial DNA, TOM translocase of outer mitochondrial membrane, OPA1 optic atrophy protein 1, MFN mitofusin, DRP1 dynamin-related protein 1, FIS mitochondrial fission protein, MFF mitochondrial fission factor, LC3B microtubule associated protein 1 light chain 3 beta, P62 sequestosome 1, PINK1 PTEN induced kinase 1, PPAR peroxisome proliferator activated receptor, PGC progastrcsin, NRF2 nuclear erythroid 2-related factor 2, TFAM transcription factor A, mitochondrial.

Figure 2

Common inflammation-related diseases of the nervous system (e.g., ischemic/reperfusion stroke, hemorrhage stroke, infectious encephalopathy, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, brain tumor). Injury manifests as neuronal damage, with intracellular mitochondrial rupture releasing DAMP such as ROS and mtDNA causing oxidative stress and inflammation in neurons. BNIP3 BCL2/adenovirus E1B 19 KDa interacting protein 3, NIX Nip3-like protein X, DRP1 Dynamin-related protein 1, ROS reactive oxygen species, mPTP mitochondrial permeability transition pore, mtDNA mitochondrial DNA, FIS mitochondrial fission protein, MFF mitochondrial fission factor, PINK1 PTEN induced kinase 1, LC3B microtubule associated protein 1 light chain 3 beta, P62 sequestosome 1, Aβ amyloid β-protein, NLRP3 NOD-like receptor protein 3, NMDA N-methyl-D-aspartic acid, AMPA α-amino-3-hydroxy-5-methyl-4-isoxazloe-propioncacid, cGAS Cyclic GMP-AMP synthase, STINGS Stimulator of interferon genes, ALOX5 Recombinant arachidonate-5-lipoxygenase, VEEV Venezuelan equine encephalitis virus, HIV-1 Human immunodeficiency virus 1, HTT Huntingtin.

Figure 3

Diagram of the mechanism of mitochondrial transport within neurons and between glial cells. Mitochondria are transported anterogradely from the cytosol to the synapse via the Miro/Milton/KIF5 complex in neuronal axons and retrogradely from the synapse to the cytosol via Dynein. Intercellular mitochondria can be directly transmitted via TNT, vesicles and intercellular contacts. Mito mitochondrion, TNT, tunneling nanotubes, Miro mitochondrial Rho, milton trafficking kinesin protein 1, KIF5 kinesin family member 5, SNPH syntaphilin.