Table 1.

Flavonoids targeting deregulated mitochondrial processes associated with cancer, CVDs, and neurodegenerative diseases in preclinical research.

Flavonoid	Mitochondrial Disorder	Study Design	Effects	Ref
Cancers
Apigenin	colon cancer	HCT116, HT29, and DLD1 colon cancer cells	↓ PKM2 activity and expression, ↓ PKM2/PKM1 ratio, blocked β-catenin/c-Myc/PTBP1	[105]
Quercetin	breast cancer	MCF-7 and MDA-MB-231 human breast cancer cell lines; murine MCF-7 xenografts	↓ PKM2, ↓ GLUT1, ↓ LDHA, ↓ p-Akt/Akt	[106]
Shikonin	lung carcinoma and melanoma	Lewis lung carcinoma and B16 melanoma cells	↓ glucose uptake, ↓ lactate production, ↓ tumor cell ATP production, ↓ PKM2	[107]
Xanthohumol	colorectal cancer	HT29, SW480, LOVO, HCT116, and SW620 colorectal cancer cell lines	↓ HK2, ↓ glycolysis, ↑ cytochrome c, ↑ intrinsic (mitochondrial) apoptotic pathway	[13]
	Glioma	rat glioma C6 cells	↓ proliferation, ↑ apoptosis, ↑ AIF	[111]
Licochalcone	colorectal cancer, non-small cell lung carcinoma, and primary bronchioalveolar carcinoma	HCT116 colorectal cancer, H1299 non-small cell lung carcinoma, and H322 primary bronchioalveolar carcinoma cells.	↓ HIF-1α, ↓ GLUT1, ↓ PDK1, ↑ intracellular oxygen content, ↓ mitochondrial respiration	[113]
EGCG	breast cancer	4T1 mouse breast cancer cells	↓ glucose, ↓ lactate, ↓ ATP levels, ↓ HIF1α, ↓ GLUT1, ↑ mitochondrial depolarization, ↓ HK, ↓ phosphofructokinase, ↓ LDH, ↓ PK	[14]
Albanol B	lung cancer	A549, BZR, H1975, and H226 human lung cancer cell lines	↑ mtROS production, ↑ phosphorylation of Akt, ↑ phosphorylation of ERK1/2, ↑ apoptosis, ↑ cell cycle arrest at G2/M phase	[114]
Lysionotin	liver cancer	HepG2 and SMMC-7721 cells and HepG2 and SMMC-7721-xenoghraft tumor mouse model	↑ mitochondrial apoptosis pathway, ↑ caspase 3, control oxidative stress	[115]
BAS-4	Glioma	C6 glioma cells	↑ apoptosis, loss of mitochondrial membrane potential, Akt pathway disruption	[116]
Isoquercetin	Melanoma	SK-Mel-2 human melanoma cells	↑ mitochondrial apoptosis, ↓ procaspase-8 and -9, ↓ Bcl-2 protein, ↑ cleaved caspase, ↑ Bax, ↑ AIF, ↑ Endo G, ↓ PI3K/Akt/mTOR signaling	[117]
Myricetin	lung cancer	in vitro (A549 lung cancer cells) and in silico study	↑ cell cycle arrest, ↑ ROS-reliant mitochondrial apoptosis	[118]
Silibinin	oral squamous carcinoma	SCC-25 human oral squamous carcinoma cells	↑ apoptosis, ↑ cytochrome c, ↑ caspase-3 and -9	[119]
Cardiovascular Diseases
Extract of Aronia melanocarpa	cardiovascular disease	50 μg/mL of Aronia Melanocarpa fruit extract in human aortic endothelial cells	↑ NF-κB, ↑ ROS production	[121]
Cornelian cherry fruits	hypertriglicerydemia and atherosclerosis	diet-induced hypertriglicerydemia and atherosclerosis in a New Zealand rabbit model	↓ serum triglyceride levels, ↑ PPARα protein expression	[123]
Naringenin	myocardial ischemia-reperfusion injury	Sprague-Dawley rats and H9c2 cardiomyoblasts	↓ mitochondrial oxidative stress damage, ↓ mitochondrial cytochrome c release, ↓ oxidative markers, ↑ mitochondrial biogenesis, ↑ NRF1, ↑ TFAM, ↑ OXPHOS II, III and IV subunits, ↓ myocardial ischemia-reperfusion injury	[15]
Naringin	cardiomyocyte hypertrophy	H9c2 rat myoblasts after fructose exposure, high fructose-induced cardiac hypertrophy	↓ mtROS production, ↓ cardiomyocyte hypertrophy, ↓ AMPK-mTOR	[124]
7,8-Dihydroxyflavone	myocardial ischemia	adult Kunming mice, H2O2-treated H9c2 Rattus norvegicus myoblasts	↓ mitochondrial fission, ↓ Fis-1, ↑ mitochondrial membrane potential, ↓ mitochondrial superoxide, ↓ OPA1	[126]
	heart disease	doxorubicin—induced cardiotoxicity in Kunming mice; H9c2 cells	↑ cardiac function, ↓ cardiac injury, ↑ OXPHOS, ↑ mitochondrial membrane potential, ↑ Akt activation, ↑ OPA1	[127]
Dihydromyricetin	diabetic cardiomyopathy	streptozotocin—induced diabetic C57BL/6J mice; dihydromyricetin treatment at 100 mg/kg/day	↑ ATP content, ↑ citrate synthase activity, ↑ complex Ι, ΙΙ, ΙΙΙ, ΙV, and V activities	[128]
Quercetin	cardiac hypertrophy	isoproterenol—induced cardiac hypertrophy in male Swiss mice	↑ protein sulfhydryls, ↑ superoxide dismutase activity, ↓ opening of mitochondrial permeability transition pore	[129]
Luteolin	sepsis-induced cardiomyopathy	intraperitoneal injection of luteolin in male C57BL/6 mice; lipopolysaccharide—induced myocardial injury	↓ mitochondrial injury, ↓ oxidative stress, ↓ phosphorylation of AMPK in septic heart tissue, ↓ destabilized mitochondrial membrane potential	[16]
Icariin	cardiac oxidative stress injury	H9C2 cardiac myocytes; H2O2—induced oxidative stress injury	↑ ROS scavenging, phosphorylation of ERK pathway, maintenance of Ca2+ homeostasis, prevention of mitochondrial membrane potential dissipation	[130]
Cyanidin	sepsis and myocardial oxidative or inflammation-induced injury	lipopolysaccharide—induced myocardial injury in male/female C57BL/6 mice	↑ mitochondrial function, ↓ oxidative damage, ↓ Opa1, ↓ Trx1	[131]
Tilialin	myocardial ischemia/reperfusion injury	oxygen-glucose deprivation/reperfusion-injured H9c2 cardiomyocytes; ischemia/reperfusion- (I/R-) injured isolated rat hearts	↑ CaMKII-mediated mitochondrial apoptosis, ↑ JNK/NF-κB inflammation	[132]
Fisetin	acute myocardial infarction	in vitro (cardiomyocytes), in vivo (rat heart model), and in silico experiment	↓ mitochondrial oxidative stress, ↓ mitochondrial dysfunction, ↓ GSK3β activity	[133]
	ischemia/reperfusion injury	Male Wistar rat model	↓ myocardial infarct size, apoptosis, lactate dehydrogenase, and creatine kinase in serum/perfusate, ↑ PI3K activation	[134]
Baicalin	myocardial injury after cardiac arrest	Cardiac arrest-induced injury in male Sprague-Dawley rats	↓ mitochondrial dysfunction, ↑ cardioprotective effect, ↓ phosphorylation at serine 616 and translocation of Drp1, and excessive fission of mitochondria	[135]
Neurodegenerative Disorders
Naringin	neurodegenerative disorders and neurotoxicity	Six-week administration of aluminum (100 mg/kg) and naringin (40 and 80 mg/kg) to male Wistar rats	↑ cognitive performance, ↓ mitochondrial oxidative damage, ↓ NADH dehydrogenase, ↓ succinate dehydrogenase, ↓ cytochrome oxidase	[137]
Quercetin	AD	Quercetin injection every 48 h for 3 months (25 mg/kg) in a murine triple transgenic AD model (3xTg-AD)	↓ Aβ, ↓ BACE1-mediated cleavage of APP	[139]
		H2O2—induced neuronal toxicity and Aβ—induced neurodegeneration of hippocampal neurons	↓ ROS, ↑ recovery of normal mitochondrial morphology	[140]
EGCG		meta-analysis of 17 preclinical studies; animal models	↓ Aβ42 level, ↓ acetylcholinesterase activity, ↓ tau phosphorylation, anti-oxidation, anti-inflammation, anti-apoptosis, ↑ α-, β-, and γ-secretase activity	[146]
Isoquercitrin		streptozotocin—induced mitochondrial dysfunction and oxidative stress in murine Neuro-2a neuroblastoma cells	↑ mitochondrial function, ↑ mitochondrial membrane potential, ↓ VDAC, ↓ mtROS	[18]
Mangiferin and morin		Aβ—induced mitochondrial impairments in cortical neurons from E18 Sprague-Dawley rat embryos	↓ mitochondrial impairments, ↑ respiratory capacity, ↓ mitochondrial membrane depolarization, ↓ cytochrome c release	[147]
Quercetin	PD	Murine MN9D dopaminergic cells; 6-hydroxydopamine—induced neurotoxicity	↑ phosphorylation of PKD1, Akt, CREB, BDNF; ↑ mitochondrial bioenergetics capacity	[143]
		6-hydroxydopamine—treated PC12 rat pheochromocytoma cells; 6-hydroxydopamine—lesioned rat model of PD	↑ mitochondrial quality control, ↓ oxidative stress, ↑ Parkin, ↑ PINK1, ↓ α-syn	[148]
		rotenone—induced rat model (inbred adult Sprague–Dawley rats)	↑ mitochondrial complex-I activity, ↓ ROS	[17]
Myricitrin		PC12 rat adrenal gland cells, 6-OHDA—induced mitochondrial damage and neurotoxicity	↓ mitochondrial damage, ↓ mitochondrial oxidation, ↓ ROS, ↓ lipid peroxidation	[149]
		1-methyl-4-phenylpyridinium—induced mitochondrial dysfunction in SN4741 substantia nigra dopaminergic cells	↑ maintenance of mitochondrial function, ↑ DJ-1	[150]
Hesperidin		rotenone—induced apoptosis in SK-N-SH neuroblastoma cells	↑ maintenance of mitochondrial function	[151]
Tilialin	cerebral ischemia	oxygen-glucose deprivation protocol; in silico docking mode and SH-SY5Y human-derived thrice cloned cell line	↑ mitochondrial function, ↓ inflammation, ↓ CaMKII-dependent mitochondrion-mediated apoptosis, ↓ MAPK/NF-κB inflammatory activation	[152]
Hydroxysafflor yellow A	ischemia/reperfusion injury	PC12 rat adrenal gland cells	↓ ROS, ↓ suppress cellular apoptosis, ↓ phenylalanine levels, ↑ mitochondrial function, ↑ upregulation of mitochondrial fission protein Drp1	[153]
	cerebral ischemia/reperfusion injury	male Sprague Dawley rats	↑ brain microvascular endothelial cells viability, ↓ ROS, ↓ opening of mitochondrial permeability transition pore, ↓ translocation of cytochrome c, ↑ phosphorylation of ERK, ↓ cyclophilin D	[154]
Nobiletin	mitochondrial dysfunction in AD and PD	mitochondrial dysfunction mediated by the ETC system downregulation by hindering complex I and III in cortical neurons of rats	↓ mtROS, ↓ apoptosis, ↑ ATP production, ↑ neuronal viability, ↓ translocation of AIF, ↑ complex I, ↑ Nrf2, ↑ HO-1	[155]

Explanatory notes: ↑ increased/improved, ↓ decreased/inhibited. Abbreviations: PKM2, protein kinase M2; c-Myc, MYC proto-oncogene; PTBP1, polypyrimidine tract binding protein 1; GLUT1, glucose transporter 1; LDHA, lactate dehydrogenase A; Akt, serine/threonine-protein kinases; ATP, adenosine triphosphate; HK2, hexokinase 2; HIF-1α, hypoxia-inducible factor 1-alpha; PDK1, phosphoinositide-dependent kinase-1; LDH, lactate dehydrogenase; PK, protein kinase; mtROS, mitochondrial reactive oxygen species; ERK1/2, extracellular signal-regulated kinases 1/2; NF-κB, nuclear factor-κB; PPARα, peroxisome proliferator-activated receptor α; NRF1, nuclear respiratory factor 1; TFAM, transcription factor A mitochondrial; OXPHOS, oxidative phosphorylation; AMPK, 5’ AMP-activated protein kinase; mTOR, mechanistic target of rapamycin; Fis-1, mitochondrial fission 1 protein; OPA1, mitochondrial dynamin like GTPase; Trx1, thioredoxin; NADH, nicotinamide adenine dinucleotide hydrogen; Aβ, amyloid beta; BACE1, beta-site APP cleaving enzyme 1; APP, amyloid-beta precursor protein; CREB, cAMP-response element binding protein; BDNF; brain-derived neurotrophic factor; tau, microtubule associated protein; AD, Alzheimer’s diseasAbbreviationse; PD, Parkinson’s disease, EGCG, epigallocatechin-3-gallate; H₂O₂, hydrogen peroxide; AIF, apoptosis-inducing factor; GSK3β, glycogen synthase kinase 3β; HO-1, heme oxygenase 1; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; Nrf2, nuclear factor erythroid 2–related factor 2; Drp1, dynamin-related protein; JNK, c-Jun N-terminal kinase.