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Review
. 2024 Aug 21;11(1):59.
doi: 10.1186/s40779-024-00556-1.

Targeting mitochondrial quality control: new therapeutic strategies for major diseases

Wei-Long Hong #  1 , He Huang #  1 , Xue Zeng #  1 , Chen-Yang Duan  2
Affiliations
Review

Targeting mitochondrial quality control: new therapeutic strategies for major diseases

Wei-Long Hong et al. Mil Med Res. .

Abstract

Mitochondria play a crucial role in maintaining the normal physiological state of cells. Hence, ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases. Previous reviews on this topic have however been inconsistencies and lack of systematic organization. Therefore, this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases. This review systematically summarizes three fundamental characteristics of mitochondrial quality control, including mitochondrial morphology and dynamics, function and metabolism, and protein expression and regulation. It also extensively examines how imbalances in mitochondrial quality are linked to major diseases, such as ischemia-hypoxia, inflammatory disorders, viral infections, metabolic dysregulations, degenerative conditions, and tumors. Additionally, the review explores innovative approaches to target mitochondrial quality control, including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality, nanomolecular materials designed for precise targeting of mitochondria, and novel cellular therapies, such as vesicle therapy and mitochondrial transplantation. This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.

Keywords: Major diseases; Mitochondrial quality control; Mitochondrial targeted therapy.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Mitochondrial quality control in the context of major diseases. Specific manifestations of major diseases, including ischemia-hypoxia, inflammatory disorders, viral infections, metabolic dysregulations, and degenerative conditions and tumors. Abnormalities in key aspects (e.g., mitochondrial morphology and dynamics, function and metabolism, and protein expression) impact the occurrence and development of various major diseases. MDV mitochondria-derived vesicle, HIV human immunodeficiency virus, COVID-19 coronavirus disease 2019, UCP uncoupling protein, NCLX mitochondrial Na+/Ca2+ exchanger, MCU mitochondrial calcium uniporter, MMP mitochondrial membrane potential, Cyt C cytochrome C, ROS reactive oxygen species, mPTP mitochondrial permeability transition pore, ANT adenosine nucleotide translocase, CYPD cyclophilin D, VDAC voltage-dependent anion channel, CPT carnitine palmitoyltransferase, CoA coenzyme A, LIPIN1 lipin 1, PA phosphatidic acid, TCA tricarboxylic acid, ADP adenosine diphosphate, ATP adenosine triphosphate, CPS1 carbamoyl-phosphate synthase 1, OMM outer mitochondrial membrane, IMM inner mitochondrial membrane, OTC ornithine transcarbamylase, ETC electron transport chain, SKP2 S-phase kinase associated protein 2, TOM translocase of outer mitochondrial membrane, VCP valosin containing protein, HSP heat shock protein, CLPXP Caseinolytic protease X and protease P complex, LONP Lon peptidase, MAV mitochondrial antiviral-signaling protein, mtUPR mitochondrial unfolded protein response, mRNA messenger RNA, GR glucocorticoid receptor, ER estrogen receptor, AR androgen receptor, GRE glucocorticoid response element (used here as an example for other gene regulatory elements), PAH pulmonary arterial hypertension, mtDNA mitochondrial DNA
Fig. 2
Fig. 2
Therapeutic strategies targeting mitochondrial quality control. Effective interventions and treatment strategies targeting mitochondrial quality control in major diseases through small molecule drugs, nanomolecular materials, and novel cell therapy approaches. CsA cyclosporin A, BAY 87–2243 an inhibitor of hypoxia-induced gene activation, Ru360 an oxygen-bridged dinuclear ruthenium amine complex, GRE glucocorticoid response element (used here as an example for other gene regulatory elements), mtDNA mitochondrial DNA, CB-5083 an inhibitor of the p97 AAA ATPase, BT317 a dual LONP1 and chymotrypsin-like proteasome inhibitor, SKPin C1 a highly selective inhibitor of S-phase kinase associated protein 2, PROTAC proteolysis-targeting chimera, SD-169 a selective inhibitor of p38α MAPK, JG98 an allosteric modulator of heat shock protein 70, Mdivi-1 mitochondrial division inhibitor-1, S89 an agonist of mitofusin 1, Pae paeonol, ZLN005 an agonist of PGC-1α, TPP triphenylphosphonium, MTPP-PEG-biotin SANs biotin-conjugated pegylated photosensitizer self-assembled nanoparticles, SS szeto-schiller, MPPs mitochondrial penetrating peptides, MTSs mitochondrial targeting signal peptides, OMM outer mitochondrial membrane, IMM inner mitochondrial membrane
Fig. 3
Fig. 3
Mind mapping for therapeutic strategies targeting mitochondrial quality control. Therapeutic strategies aimed at enhancing mitochondrial quality control predominantly center on two key facets: small molecule drugs that modulate pivotal processes governing mitochondrial quality encompassing morphology and dynamics, function and metabolism, as well as protein expression and regulation; and innovative approaches to mitochondrial therapy, which encompass the utilization of nanomaterials and novel cellular therapies. ROS reactive oxygen species, mPTP mitochondrial permeability transition pore, OXPHOS oxidative phosphorylation, TCA tricarboxylic acid, MAD mitochondrial associated degradation, UPS ubiquitin–proteasome system, Mitoproteases mitochondrial protease system, MSC mesenchymal stem cell, Mdivi-1 mitochondrial division inhibitor-1, P110 a specific inhibitor of dynamin-related protein 1, S89 an agonist of mitofusin 1, MASM7 a serine protease activator, ZLN005 an agonist of PGC-1α, SR3677 Rho kinase inhibitor, Ru360 an oxygen-bridged dinuclear ruthenium amine complex, MCU-i4 mitochondrial calcium uniporter inhibitor, NAC N-acetyl-L-cysteine, BAY 87–2243 an inhibitor of hypoxia-induced gene activation, NMS-873 an allosteric inhibitor of p97, CB-5083 an inhibitor of the p97 AAA ATPase, SKPin C1 a highly selective inhibitor of S-phase kinase associated protein 2, SZL P1-41 specific inhibitor of S-phase kinase-associated protein 2, PROTACs proteolysis-targeting chimeras, ARV-766 luxdegalutamide, BT317 a dual LONP1 and chymotrypsin-like proteasome inhibitor, 334 an AAA ATPase inhibitor, C86 and JG98 allosteric modulators of heat shock protein 70, CoQ coenzyme Q, TPP-PEG-PCL triphenylphosphonium-poly(ethylene glycol)-poly(ε-caprolactone) polymers, Lip-SPG multi-targeted redox-sensitive liposomes, SS szeto-schiller
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