Targeting mitochondrial quality control: new therapeutic strategies for major diseases

Hong, Wei-Long; Huang, He; Zeng, Xue; Duan, Chen-Yang

doi:10.1186/s40779-024-00556-1

Military Medical Research

Table 2 Small molecule drugs targeting mitochondrial quality control

From: Targeting mitochondrial quality control: new therapeutic strategies for major diseases

Small molecule drug	Targeted protein	Targeting step	Research state	Reported disease models	References
Mdivi-1	DRP1	Fission	Preclinical phase	Cardiac arrest, heart failure, myocardial infarction, neurodegenerative diseases, acute kidney injury, and cerebral ischemia–reperfusion	[166,167,168,169,170,171,172]
P110	DRP1	Fission	Preclinical phase	Myocardial ischemia–reperfusion, sepsis-induced myocardial disease, PAH, sepsis-induced brain dysfunction, neurodegenerative diseases, and ALS	[25, 172,173,174,175,176,177,178]
Dynasore	DRP1	Fission	Preclinical phase	Spinal cord injury, myocardial ischemia–reperfusion, type 2 diabetes, and PD	[166, 179,180,181,182]
15-oxospiramilactone (S3)	MFN1/2	Fusion	Preclinical phase	Type 2 diabetes	[183, 184]
S89	MFN1	Fusion	Preclinical phase	Myocardial ischemia–reperfusion	[185]
MASM7	MFN2	Fusion	Preclinical phase	Spinal cord injury	[186, 187]
Paeonol (Pae)	OPA1	Fusion	Preclinical phase	Inflammation, pain-related diseases, oxidative damage, diabetic cardiomyopathy, cardiovascular diseases, PAH, AD, dentine hypersensitivity, and soft tissue injury	[188,189,190,191,192]
ZLN005	PGC-1α	Biogenesis	Preclinical phase	Diabetes, neuroprotection, retinal protection, renal ischemia–reperfusion, and high glucose-induced cardiomyopathy	[193,194,195,196,197]
Kinetin	PINK1	Mitophagy	Phase I clinical trial (NCT02274051)	Familial dysautonomia	[198]
Kinetin	PINK1	Mitophagy	Phase IV clinical trial (NCT01898182)	Skin photoaging	[198]
Kaempferol	PINK1	Mitophagy	Phase I clinical trial (NCT06060691)	Female arousal disorder and sexual dysfunction	[199]
Kaempferol	PINK1	Mitophagy	Preclinical phase	AD	[199]
Rhapontigenin	PINK1	Mitophagy	Preclinical phase	AD	[199]
SR3677	PARKIN	Mitophagy	Preclinical phase	Paraquat poisoning	[200]
Cyclosporin A (CsA)	/	mPTP channel	Phase II clinical trial (NCT01650662)	Reperfused acute myocardial infarction	[201,202,203,204,205]
Cyclosporin A (CsA)	/	mPTP channel	Preclinical phase	Pulmonary ischemia–reperfusion, hemorrhagic shock, and solid organ transplantation	[201,202,203,204,205]
Ru360	/	Calcium ion channel	Preclinical phase	Myocardial ischemia–reperfusion, traumatic brain injury	[206, 207]
MCU-i4	/	Calcium ion channel	Preclinical phase	Cancer, pancreatitis, and heart failure	[208]
N-acetyl-L-cysteine (NAC)	/	ROS generation	Approved for listing	Dietary supplement	[209,210,211]
N-acetyl-L-cysteine (NAC)	/	ROS generation	Preclinical phase	Drug-induced liver injury, COVID-19, and PD	[209,210,211]
Genipin	/	ROS generation	Phase III clinical trial (NCT05755750)	Horses with tendon injuries	[212, 213]
Genipin	/	ROS generation	Preclinical phase	Breast cancer, gastric cancer, liver cancer, and other tumor models, and tendon injuries	[212, 213]
Vitamins C and E	/	ROS generation	Approved for listing	Dietary supplement	[214, 215]
Vitamins C and E	/	ROS generation	Preclinical phase	Peripheral nerve damage, dysmenorrhea, and pelvic pain	[214, 215]
Resveratrol	/	ROS generation	Approved for listing	Dietary supplement	[216, 217]
Resveratrol	/	ROS generation	Preclinical phase	Hypertension, diabetes, and tumor	[216, 217]
BAY 87–2243	/	OXPHOS	Phase I clinical trial (NCT01297530)	Advanced malignancies	[218, 219]
BAY 87–2243	/	OXPHOS	Preclinical phase	Lung cancer and melanoma	[218, 219]
Antimycin A	/	OXPHOS	Preclinical phase	Cervical carcinoma	[220]
Tetrathiomolybdate	/	OXPHOS	Phase II clinical trial (NCT00195091)	Breast cancer	[221]
Tetrathiomolybdate	/	OXPHOS	Preclinical phase	Ovarian cancer, endometrial cancer, and non-small cell lung cancer	[221]
CPI-613 (devimistat)	/	TCA cycle	Phase I/II clinical trial (NCT04593758)	Relapsed or refractory clear cell sarcoma of soft tissue	[222, 223]
			Phase II clinical trial (NCT05733000)	Advanced chemorefractory solid tumors
			Phase II clinical trial (NCT05854966)	Relapsed or refractory acute myeloid leukemia (AML)
			Phase III clinical trial (NCT03504410)	Relapsed or refractory acute myeloid leukemia (AML)
			Phase II clinical trial (NCT04217317)	Refractory T-cell non-hodgkin lymphoma
			Phase I/II clinical trial (NCT04203160)	Advanced unresectable biliary tract cancer (Bilt-04)
Elamipretide	/	Phospholipid synthesis	Phase III clinical trial (NCT05162768)	Primary mitochondrial disease from nuclear DNA mutations (Npmd) (Nupower)	[224,225,226]
Elamipretide	/	Phospholipid synthesis	Preclinical phase	Primary mitochondrial myopathy, traumatic brain injury	[224,225,226]
Ketogenic agents	/	Ketone metabolism	—	Cardiovascular disease	[15]
L-carnitine	/	Fatty acid β-oxidation	Approved for listing	Dietary supplement	[227, 228]
L-carnitine	/	Fatty acid β-oxidation	Preclinical phase	Cardiovascular diseases, hypertension, hyperlipidemia, type 2 diabetes, and obesity	[227, 228]
NMS-873	/	MAD	Preclinical phase	Ovarian cancer	[17, 18, 229]
CB-5083	/	MAD	Phase I clinical trial (NCT02243917)	Advanced solid tumors	[17, 18, 229]
CB-5083	/	MAD	Preclinical phase	Lymphoid system malignancies	[17, 18, 229]
SKPin C1	/	UPS	Preclinical phase	Melanoma and myeloma	[230, 231]
SZL P1-41	/	UPS	Preclinical phase	Renal cancer, leukemia, glioma, and lung tissue fibrosis	[232,233,234,235]
PROTACs	/	UPS	—	Cancer, diabetic cardiomyopathy, and chronic myeloid leukemia	[236,237,238,239]
ARV-766	/	UPS	Phase II clinical trial (NCT05067140)	Prostate cancer	[240]
BT317	/	Mitoproteases and chaperonin	Preclinical phase	Tumor	[241]
334	/	Mitoproteases and chaperonin	Preclinical phase	Leukemia	[242]
SD-169 (5-carbamoylindole)	/	Mitoproteases and chaperonin	Preclinical phase	Diabetes	[243]
C86 (chalcone)	/	Mitoproteases and chaperonin	Phase II clinical trial (NCT06063655)	Prostate cancer	[244]
JG98	/	Mitoproteases and chaperonin	Preclinical phase	Prostate cancer	[244]
CoQ	/	Mitochondrial signaling	Approved for listing	Dietary supplement	[245,246,247]
CoQ	/	Mitochondrial signaling	Preclinical phase	Acute kidney, lung, and septic liver injuries	[245,246,247]
α-lipoic acid	/	Mitochondrial signaling	Approved for listing	Dietary supplement	[248]
α-lipoic acid	/	Mitochondrial signaling	Preclinical phase	Sepsis	[248]
Nicotinic acid (vitamin B3)	/	Mitochondrial signaling	Approved for listing	Dietary supplement	[249]
Nicotinic acid (vitamin B3)	/	Mitochondrial signaling	Preclinical phase	Sepsis-induced liver injury	[249]
Mifepristone	/	Mitochondrial signaling	Approved for listing	Type 2 diabetes, Cushing’s syndrome, and adenomyosis	[250, 251]
17β-estradiol	/	Mitochondrial signaling	Approved for listing	Cerebral ischemia	[252]
Bicalutamide (Bic, ICI-176334)	/	Mitochondrial signaling	Approved for listing	Tumors, such as prostate cancer	[253, 254]

AD Alzheimer’s disease, PD Parkinson’s disease, COVID-19 coronavirus disease 2019, 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, 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, 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 are allosteric modulators of heat shock protein 70, CoQ coenzyme Q, DRP1 dynamin-related protein 1, PAH pulmonary arterial hypertension, ALS amyotrophic lateral sclerosis, MFN mitofusin, OPA1 optic atrophy protein 1, PGC-1α peroxisome proliferator-activated receptor gamma coactivator-1α, PINK1 phosphatase and tensin homolog (PTEN)-induced kinase 1, PARKIN parkinson protein 2 E3 ubiquitin protein ligase. Dietary supplements have been approved by the U.S. Food and Drug Administration (FDA, https://www.fda.gov/)

Back to article page

ISSN: 2054-9369

Contact us

Submission enquiries: Access here and click Contact Us
General enquiries: journalsubmissions@springernature.com

You are viewing the site in preview mode

Military Medical Research

Contact us