Part2: Protective Effects Of Flavonoids Against Mitochondriopathies And Associated Pathologies: Focus On The Predictive Approach And Personalized Prevention

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4. Protective Effects of Flavonoids against Pathologies Associated with Mitochondriopathies

Regular consumption of flavonoids exerts beneficial health effects that can potentially be utilized against several mitochondriopathies, including cancers, CVDs such as atherosclerosis, and neurodegenerative disorders such as AD [103,104].

4.1.Preclinical Research

Various in vitro and in vivo studies evaluated the efficacy of flavonoids in mitochondria-associated impairments and/or diseases.

4.1.1.Cancer

Preclinical cancer research demonstrated the potent capacity of flavonoids to modulate pro-carcinogenic mitochondrial dysfunction, especially in signaling cascades associated with the Warburg phenotype and the intrinsic apoptotic pathway. Apigenin (4',5,7-trihydroxyflavone) blocked cellular glycolysis by inhibiting tumor-specific PKM2 activity and expression in HCT116, HT29, and DLD1 colon cancer cells. Moreover, apigenin treatment decreased the PKM2/PKM1 ratio by blocking the β-catenin/c-Myc/PTBP1 signaling pathway [105]. Furthermore, quercetin suppresses glycolysis by downregulating PKM2, glucose transporter 1(GLUT1), and lactate dehydrogenase A(LDHA) in MCF-7 and MDA-MB-231 human breast cancer cell lines. Additionally, quercetin treatment inhibited glycolysis and induced autophagy by inhibiting p-Akt/Akt in murine MCF-7 xenografts [106]. Moreover, shikonin treatment inhibited glucose uptake, lactate production, and ATP production in Lewis lung carcinoma and B16 melanoma cells by decreasing PKM2 activity and consequently reversing the Warburg effect [107]. Furthermore, the enzyme hexokinase 2(HK2) converts glucose to glucose-6-phosphate in the first step of glucose metabolism [108] and promotes the Warburg effect in cancer cells [109]. However, xanthohumol downregulated HK2 and glycolysis and subsequently increased cytochrome c release to activate the intrinsic (mitochondrial) apoptotic pathway in the HT29, SW480, LOVO, HCT116, and SW620 colorectal cancer cell lines [13]. The apoptosis-inducing factor (AF), a mitochondrial protein, is implicated in caspase-independent programmed cell death following its translocation to the nucleus [110]. In an in vitro investigation using multiple biochemical assays, xanthohumol was detected to cause proliferation inhibition and death of the rat glioma C6 cells (in a time- and dose-dependent manner) via a mechanism of inducing AIF pathway apoptosis by triggering mitochondrial stress [111]. Impressively, pyruvate dehydrogenase kinase 1(PDK1)is a gatekeeper of glycolysis and mitochondrial OXPHOS; its inhibition can reverse the Warburg phenotype of tumor cells [112]. Lic-chalcone A suppressed HIF1α, GLUT1, and PDK1 in HCT116 colorectal cancer, H1299 non-small cell lung carcinoma, and H322 primary bronchioalveolar carcinoma cells. Be-sides, higher intracellular oxygen content resulting from the direct inhibition of mitochondrial respiration was observed after licochalcone A treatment [113]. Furthermore, EGCG promoted mitochondrial depolarization and suppressed glycolysis in 4T1 murine breast cancer cells, as demonstrated through reduced levels of glucose, lactate, ATP, HIF-1α, and GLUT1. EGCG also inhibited several glycolytic enzymes, including HK, phosphofructokinase, LDH, and PK, in the same model [14]. Moreover, Albano B, a benzofuran flavonoid, exerted potent anti-cancer effects by inducing apoptosis through mtROS production and associated increased phosphorylation of Akt and extracellular signal-regulated kinase 1/2(ERK1/2)in A549, BZR, H1975, and H226 human lung cancer cell lines. The anti-cancer potential of Albano B was associated with the induction of apoptosis and G2/M phase cell cycle arrest through mtROS production [114]. Lysionotin, a bioactive flavonoid from Li/sionofus pauciflorus Maxim., has been shown in a combined in vitro (HepG2 and SMMC-7721 cells) and in vivo (HepG2 and SMMC-7721-xenograft tumor mouse model)experiment the ability to exert remarked anti-liver cancer properties through a mechanism that causes caspase-3 mediated mitochondrial apoptosis pathway. The outcomes of this study have also revealed that lysionotin could control oxidative stress, which was found to be involved in lysionotin-mediated mitochondrial apoptosis by regulating the nuclear factor erythroid 2-related factor2 (Nrf2) signaling pathway[115]. BAS-4, a prenylated flavonoid (isolated from the Amazon plant Brosimum acutifolium), was observed to cause anticancer properties against the C6 glioma cells by promoting apoptosis mediated by mitochondrial transmembrane potential loss and Akt pathway disruption [116]. Furthermore, treatment with isoquercitrin （25 μM）， a bioactive flavonol， exhibited anti-cancer effects against SK-Mel-2 human melanoma cells, and the mechanism was observed to be related to its effect on mitochondria-mediated apoptosis. Various mechanisms were reported, including the reduction in the levels of procaspase-8 and-9, and Bcl-2 protein, and the enhancement of cleaved PARP and Bax expressions. The caspase-independent mitochondrial-mediated apoptosis was found to be linked to the increase of AIF and Endo G protein expressions. Besides, the anti-proliferative activity was determined to be associated with the downregulation of the PI3K/Akt/mTOR signaling pathway[117]. In a mechanistic study using in vitro(A549 cells)and in silico assays, the flavonoid myricetin (73ug/mL)showed the capacity to induce anticancer properties against lung cancer cells by promoting cell cycle arrest and ROS-reliant mitochondria-facilitated apoptosis [118]. Moreover, the flavonoid silibinin, a bioactive substance from Silybum marianum, exerted a cytotoxic effect against SCC-25 human oral squamous carcinoma cells. The in vitro assay disclosed the mechanism of action via inducing apoptosis by releasing mitochondrial cytochrome c into the cytosol followed by activating caspases-3 and -9 [119].

As demonstrated in the above-discussed preclinical studies, flavonoids have the potential to reverse the Warburg effect by targeting signaling molecules associated with mitochondrial respiratory defects. Moreover, the anti-Warburg effect of flavonoids could be multiplied by an antioxidant, anti-inflammatory, ROS scavenging, immunomodulatory, anti-angiogenic [82], and other anti-cancer activities such the participation in cell cycle arrest, apoptosis induction, autophagy, and suppression of cancer cell proliferation and invasiveness [83].

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4.1.2. Cardiovascular Diseases

Flavonoids potently affect the complex pathways associated with CVD-related mitochondrial dysfunctions. Nuclear factor-kB(NF-kB), a transcription factor, regulates many cellular processes, including immunity, inflammation, and cell survival. Besides, NF-kB signaling is also essential for mitochondrial processes, such as biogenesis, metabolism, and apoptosis [120]. Further, NF-kB is a redox-sensitive transcription factor because ROS can regulate its activity. An extract of Aronia melanocarpa rich in polyphenols, especially anthocyanins, activated NF-kB by ROS production in human aortic endothelial cells (HAECs), resulting in potential cardioprotection [121]. Moreover, the peroxisome proliferation-activated receptor(PPAR) family regulates mitochondrial function, turnover, and energy metabolism. Therefore, PPAR activity can represent a therapeutic target to restore impaired mitochondrial function [122]. Cornelian cherry(Cornus mas L.) fruits rich in anthocyanins, phenolic acid, flavonols, and iridoids decreased serum triglyceride levels and increased PPARa protein expression in the liver, suggesting protective effects on diet-induced hypertriglyceridemia and atherosclerosis in a hypercholesterolemic rabbit model. Moreover, increased expression of PPAR in the liver indicated its hypolipidemic effect obtained from enhanced fatty acid catabolism which subsequently led to decreased triglyceride levels [123].

Interestingly, mitochondrial dysfunction contributes to myocardial ischemia-reperfusion-induced cardiomyocyte apoptosis. Yu et al. recently reported that naringenin can alleviate myocardial ischemia-reperfusion injury by reducing mitochondrial oxidative stress damage, cytochrome c release, and oxidative markers. Moreover, mitochondrial biogenesis was maintained by increased nuclear respiratory factor 1(NRF1), TFAM, and OXPHOS I, ⅡII, and IV subunit complexes in vitro (H9c2 cardiomyoblasts) and in vivo (rats)models [15].

Moreover, mitochondrial dysfunction has a crucial role in the pathogenesis of fructose-induced cardiac hypertrophy. The bioflavonoid naringin inhibited mtROS production and thereby relieved mitochondrial dysfunction in H9c2 rat myoblasts after fructose exposure and high fructose-induced cardiac hypertrophy. Indeed, the suppression of cardiomyocyte hypertrophy by naringin was mediated through downregulation of the AMP-activated protein kinase (AMPK)-the mechanistic target of the rapamycin (mTOR) signaling axis [124]. Furthermore, proteins involved in mitochondrial dynamics, including mitofusin 2(Mfn2), mitochondrial dynamin-like GTPase(OPA1), dynamin-related protein 1(Drp1), and fission 1(Fis-1), regulate mitochondrial homeostasis under stress conditions [125]. Treatment of myocardial ischemic mice with 7,8-dihydroxyflavone (7,8-DHF)reversed cardiac dysfunction and cardiomyocyte abnormalities through the suppression of mitochondrial fission, as demonstrated by decreased protein levels of Fis-1. Besides,7,8-DHF improved the mitochondrial membrane potential and reduced mitochondrial superoxide levels in hydrogen peroxide (H2O2)-treated H9c2 rat myoblasts.7,8-DHF also prevents mitochondrial fission by inhibiting proteolytic cleavage of OPA1 in H9c2 cells [126]. Similarly, 7,8-DHF improved cardiac function and inhibited cardiac injury mediated by increased OPAl protein expression, Akt activation, OXPHOS, and mitochondrial membrane potential dysregulation in doxorubicin-induced cardiotoxicity in Kunming mice and H9c2 cells [127].

In many cases, diabetic cardiomyopathy causes heart failure. Dihydromyricetin increased mitochondrial function in streptozotocin-induced diabetic mice, as demonstrated by increases in ATP content, citrate synthase activity, and complex I, II, I, IV, and V activities[128]. Moreover, quercetin protected mitochondria by restoring the cellular redox balance after isoproterenol-induced cardiac hypertrophy in mice. Quercetin attenuated cardiac hypertrophy by increasing sulfhydryl group availability and mitochondrial superoxide dismutase activity and reducing mitochondrial permeability transition pore opening in the same model [129]. Impressively, intraperitoneal injection of luteolin in mice with lipopolysaccharide-induced myocardial injury mitigated mitochondrial injury and oxidative stress by decreasing AMPKphosphorylation in septic heart tissue and stabilizing the mitochondrial membrane potential. In summary, luteolin attenuates lipopolysaccharide-induced myocardial injury associated with mitochondrial impairments in mice through the inhibition of apoptosis and enhancing autophagy via modulation of AMPK signaling [16]. Furthermore, icariin, a prenylated flavonol glycoside, protected H9C2 cardiomyocytes from oxidative stress by scavenging ROS and promoting ERK pathway phosphorylation. Icarian also preserved Ca2+ homeostasis and mitochondrial membrane potential stability [130]. Moreover, cyanidin, an anthocyanin pigment, improved mitochondrial function in mice with lipopolysaccharide-induced myocardial injury by reducing oxidative damage through the associated factor Opal and the antioxidant gene thioredoxin-1 (Trx1)[131]. Tilianin, a natural flavonoid glycoside, is known for its cardioprotective effect against myocardial ischemia/reperfusion injury (MIRI).In a comprehensive preclinical study, the mechanism of action of this compound has been determined through hindering Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated mitochondrial apoptosis and c-Jun N-terminal kinase (JNK)/NF-kBinflammation [132]. Moreover, the cardioprotective effect of fisetin, a natural flavonoid, has been comprehensively investigated in a combined experiment(in vitro, in vivo, and in silico). The results showed that treatment with fisetin could suppress mitochondrial oxidative stress and mitochondrial dysfunction and repress glycogen synthase kinase 3β(GSK3β)activity, where the induced effects were reported as possible mechanisms of action [133]. In another animal study, the administration of fisetin (20 mg/kg) attenuated the myocardial infarct size, apoptosis, lactate dehydrogenase, and creatine kinase in serum/perfusate of the rat hearts subjected to ischemia/reperfusion injury. The results concluded that phosphoinositide 3-kinase(PI3K)activation is needed to mediate fisetin-associated cardioprotection against ischemia/reperfusion injury in rat hearts [134]. Furthermore, phosphorylation of Drpl at serine 616 is associated with increased Drpl enzyme activities that consequently contribute to cell death. It is known that myocardial injury after cardiac arrest(CA) leads to critical myocardial dysfunction and

death, including mitochondrial dysfunction. In this regard, baicalin, a natural flavonoid molecule, was studied in vivo for its cardioprotection against CA-induced injury by regulating mitochondrial dysfunction. Male Sprague-Dawley rats were treated with baicalin (100 mg/kg, administered intragastrically once daily for 4 weeks)and the results proved that this compound has potently reduced mitochondrial dysfunction and exhibited cardioprotective effect after CA by a mechanism via inhibiting the phosphorylation at serine 616 and translocation of Drp1 and excessive fission of mitochondria. In conclusion, the inhibition of Drp1-mediates mitochondrial fission might be the possible mechanism of baicalin in preventing CA-induced myocardial injury [135].

Several preclinical (in vitro and in vivo)studies indicate that flavonoids can reverse CVD-associated mitochondriopathies by targeting various molecules and signaling pathways.

4.1.3. Neurodegenerative Disorders

Aluminum, a neurotoxicant, causes oxidative damage as observed in various neurodegenerative disorders such as AD [136]. However, naringin reduced the neurotoxic effects of aluminum in rats. The administration of a higher dose of naringin (80 mg/kg)significantly improved cognitive performance, reduced mitochondrial oxidative damage, and downregulated certain mitochondrial enzymes, including NADH dehydrogenase, succinate dehydrogenase, and cytochrome oxidase, compared to control aluminum-treated rats [137. APP and Aβ co-localize in mitochondria; Aβ inhibits the respiratory chain, and altered mitochondrial function can result in changes in APP and eventual alterations in the production of amyloidogenic derivatives [138]. Nevertheless, quercetin reduced Aβ and BACE1-mediated cleavage of APP in a murine triple transgenic AD model (3xTg-AD)[139]. Treatment with quercetin also decreased ROS levels and restored normal mitochondrial morphology in hippocampal neurons affected by H2O2-induced neuronal toxicity, and Aβ-induced neurodegeneration this suggests that quercetin could prevent neuronal mitochondrial dysfunction [140].

Furthermore, quercetin upregulated protein kinase D1(PKD1), Akt, cAMP response-element binding protein(CREB), and the CREB target gene BDNF—all of which are associated with mitochondrial dysfunction related to neurodegenerative disorders [141,142]—-in murine MN9D dopaminergic cells. Besides, quercetin increased the mitochondrial bioenergetic capacity and protected MN9D cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity [143]. Interestingly, acetylcholinesterase activity causes mitochondrial impairments; however, cholinesterase inhibitors increase mitochondrial biogenesis through AMP-Activated PK in the hippocampus [144]. Mitochondrial y-secretase participates in the metabolism of mitochondria-associated APP [145]. In this regard, a meta-analysis of 17 preclinical studies on AD animal models revealed that EGCG exerts neuroprotective effects by reducing acetylcholinesterase activity, enhancing α-,β-, and y-secretase activity, decreasing Aβ42 levels and tau phosphorylation, and modulating anti-oxidative, anti-inflammatory, and anti-apoptotic processes [146]. Moreover, the flavonoid isoquercitrin enhanced mitochondrial function by attenuating mitochondrial membrane potential loss, downregulating the outer mitochondrial membrane voltage-dependent anion channel (VDAC), and preventing mtROS accumulation in a model of streptozotocin-induced AD in murine Neuro-2a neuroblastoma cells [18]. Two other flavonoids, mangiferin, and morin alleviated Aβ-induced mitochondrial impairments such as decreased respiratory capacity, mitochondrial membrane depolarization, and cytochrome c release in cortical neurons in the AD model [147].

Quercetin increased mitochondrial complex I activity(demonstrated by increased NADH oxidation), constraining mtROS production in a rotenone-induced rat model of PD[17]. Recently, the neuroprotective effect of quercetin has been investigated in 6-OHDA-treated PC12 rat pheochromocytoma cells and the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD. The outcomes of in vitro assay showed that treatment with quercetin (20 uM)promoted mitochondrial quality control, diminished oxidative stress, boosted the levels of the mitophagy markers (Parkin and PINK1), and lowered α-syn protein expression in6-OHDA-treated PC12 cells. Moreover, the results of in vivo test proved that treatment of PD rats with quercetin (10 mg/kg/day and 30 mg/kg/day)for two weeks by oral gavage has led to producing progressive PD-like motor behaviors, alleviate neuronal death, and lessen mitochondrial damage and α-syn accumulation. All experimental results assumed that the neuroprotective effect of quercetin was defeated by the knockdown of both PINK1 and Parkin[148]. Furthermore, in PC12 rat adrenal gland cells, the naturally occurring hydroxy flavonoid myricitrin ameliorated 6-OHDA-induced mitochondrial damage through the inhibition of mitochondrial oxidation, as demonstrated by reduced ROS production and lipid peroxidation in rat brain mitochondria [149]. Myricitrin also mitigated mitochondrial dysfunction by increasing DJ-1 activity in SN4741 substantia nigra dopaminergic cells with 1-methyl-4-phenylpyridinium-induced mitochondrial dysfunction [150]. Another study revealed that hesperidin, a citrus flavanol, exerted antioxidative and antiapoptotic properties by maintaining mitochondrial function against rotenone-induced apoptosis in an SK-N-SH neuroblastoma cellular model of PD [151].

The mechanism of the neuroprotective effect of Italiani against cerebral ischemia using oxygen-glucose deprivation(OGD) protocol was detailed, where Italiani was found to affect mitochondrial function and inflammation by alleviating CaMKII-dependent mitochondrion-mediated apoptosis and MAPK/NF-kB inflammatory activation follow-ing cellular OGD injury [152]. In traditional Chinese medicine, hydroxysafflor yellow A (HSYA; a C-glucosylquinochalcone that belongs to the flavonoid family) has been widely employed as a protective agent against ischemia/reperfusion injury. This compound has also been noticed to reduce the levels of ROS and suppress cellular apoptosis. In a mechanistic study, HSYA was found to decrease phenylalanine levels and promote mitochondrial function via the upregulation of mitochondrial fission protein Drp1, leading to causing a neuroprotective effect against cerebral ischemia/reperfusion injury [153]. A recent in vivo study using male Sprague Dawley rats was designed to assess the protective effects of HSYA-mediated mitochondrial permeability transition pore (mPTP) on cerebral ischemia/reperfusion injury and its mechanism. The obtained results indicated that HSYA treatment remarkably enhanced brain microvascular endothelial cells (BMECs)viability, lowered the production of ROS, the opening of mPTP, and translocation of cytochrome c. HSYA was also detected to potentiate MEK and boost phosphorylation of ERK expression in BMECs, hinder apoptosis mediated by mitochondrial, and repress cyclophilin D(CypD). Interestingly, HSYA has been found to decrease the infarct size in animal models[154]. Nobiletin, a polymethoxylated flavonoid, is commonly detected in the genus Citrus. In multiple biochemical investigations, nobiletin was found to regulate mitochondrial dysfunction mediated by the ETC system downregulation by hindering complex and ⅢI in pure mitochondria and the cortical neurons of rats. This molecule at various concentrations in micromolar ranges was noticed to potently reduce mitochondrial ROS production, re-strain apoptotic signaling, improve ATP production, and improve neuronal viability under conditions of complex I repression. The induced effect was related to the downregulation of translocation of AI, the upregulation of complex I activity, and the expression of antioxidant factors such as Nrf2 and heme oxygenase 1(HO-1). Based on the acquired data, this study suggested that nobiletin might have promising neuroprotective action against neurodegenerative diseases such as AD and PD [155].

As discussed above, flavonoids can alleviate mitochondrial impairments mainly by reducing ROSor maintaining mitochondrial functions; these abilities can improve cognitive function associated with the two most common neurodegenerative disorders, AD and PD (Table 1).

4.2.Clinical Data

In addition to preclinical studies, clinical research also highlights the efficacy of flavonoids in the etiopathology of mitochondriopathies, including cancers, CVDs, and neurodegenerative disorders.

4.2.1.Cancer

Despite the beneficial effects of flavonoids elucidated in preclinical cancer studies, no clinical studies to date have directly focused on the mechanistic effects of flavonoids on mitochondrial impairments. Otto Warburg hypothesized that mitochondrial dysfunction initiates cancer formation characterized by decreased glycolytic energy production in contrast with mitochondrial respiration [156]. Targeted therapies using flavonoids against the Warburg effect could have important applications in future cancer management [157]. Flavonoid supplements could support cancer prevention, especially in high-risk individuals; key risk factors include obesity (due to low physical activity and/or sedentary lifestyle)[158,159], stress exposure [160], Flammer syndrome [161], accelerated aging processes [162], and chronic inflammation [163]. Moreover, genetic predispositions [164], the early detection of mitochondrial impairments [156], and the detection of cancer with metastatic potential]165|are highly predictive in cancer management. Therefore, individualized patient profiling is an essential tool for cancer predisposition and early diagnostics [166]. In evaluating the applications of flavonoids in patient stratification and individualized therapy, it is essential to consider the varying mechanisms underlying cancer, as cancers associated with mitochondrial impairments may differ from those associated with nuclear mutations [167-169].

Eventually, the application of plant-derived natural substances such as flavonoids alone or in combination with anticancer drugs could constitute a promising strategy against the Warburg phenotype within the 3 PM framework.

4.2.2.Cardiovascular Diseases

Mitochondria play a significant role in the pathogenesis of various CVDs. However, current clinical research aimed at finding novel molecules applicable against CVDs focuses primarily on the general protective properties of flavonoids rather than their direct impact on mitochondrial impairments.

Isoflavone treatment for 12 weeks reduced serum high-sensitivity (hs)-C-reactive protein(CRP)levels and improved brachial flow-mediated dilatation in patients with clinically manifested atherosclerosis and prior ischemic stroke [170]. Moreover, dietary intake of flavonoid-rich foods can prevent mitochondriopathies related to CVDs. Flavonoids, including flavonols, flavones, flavanones, anthocyanidins, and proanthocyanidins, significantly decreased the risk of CVD mortality[171]. Interestingly, flavonoids in black, green, herbal, and berry teas possess protective effects against various CVDs, including stroke, myocardial infarction, and coronary heart diseases [172].

Moreover, transthyretin amyloidosis is a rare progressive systemic disease characterized by increased left ventricular wall thickness and diastolic dysfunction. In many cases, this disease leads to amyloidotic transthyretin mitochondrial cardiomyopathy [173]. After 12 months of treatment with green tea and its extracts, in which EGCG is abundant, echocardiography revealed no changes in cardiac wall thickness and mass progression, suggesting that green tea exerts protective effects against amyloidotic transthyretin mitochondrial cardiomyopathy [174]. Furthermore, menopause in women is often related to the aging process and higher CVD risk with possible mitochondrial connections [175,176]. In women with early menopause, supplementation with soy protein and isoflavones significantly decreased various CVD risk markers [177].

Moreover, altered mitochondrial functions also cause hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure, collectively known as metabolic syndrome [178]. Blueberries rich in flavonoids decreased plasma oxidized low-density lipoprotein (LDL), serum malondialdehyde, and hydroxynonenal concentrations in patients with metabolic syndrome. These results suggest that blueberries have cardioprotective effects and alleviate metabolic syndrome [179]. Furthermore, cranberries (Vaccinium macrocarpon Ait.)rich in polyphenols, including flavonoids and ellagic acid, increased plasma antioxidant capacity and reduced lipid oxidation by decreasing oxidized LDL and malondialdehyde in women with metabolic syndrome [180].

Furthermore, mitochondrial structure and/or function alterations are associated with a higher risk of various CVDs, including ischemic cardiomyopathy, heart failure, and stroke [53]. Therefore, higher intake of fruit-based flavonoids, especially through anthocyanin-rich(cyanidin, delphinidin, malvidin, pelargonidin, petunidin, peonidin)and flavanone-rich(eriodictyol, hesperetin, naringenin) foods, reduced the risk of nonfatal myocardial infarction and ischemic stroke in men [181]. Flavonoids also have potential in the secondary prevention of ischemic heart disease. Flavonoids in chokeberry (Aronia melanocarpa)extract reduced serum 8-isoprostane, oxidized LDL, hsCRP, and monocyte chemoattractant protein-1 (MCP-1) levels and increased adiponectin levels in patients who survived myocardial infarction and had received statin therapy [182]. In conclusion, current clinical studies provide predominantly general data on the efficacy of flavonoids against CVDs rather than precise mechanisms related to mitochondrial function.

4.2.3. Neurodegenerative Disorders

Neurodegenerative disorders are closely associated with mitochondrial deregulation [69]. Flavonoids can potently attenuate the negative impact of mitochondrial dysfunction on the pathogenesis of neurodegenerative disorders, as shown by preclinical research.

However, current clinical studies primarily offer results dealing with the general effects of flavonoids on neurodegenerative diseases. Increased cellular oxidative stress leads to α-syn accumulation and subsequently to mitochondrial dysfunction [183]. The flavonoid EGCG inhibits α-syn aggregation and reduces associated toxicity. Therefore, EGCG treatment can potentially delay or prevent various mitochondriopathies associated with neurodegenerative disorders [184]. However, EGCG treatment did not modify the progression of multiple system atrophy, a neurodegenerative disease associated with α-syn aggregation in neurons and oligodendrocytes. In addition, higher doses(1200 mg) were connected to hepatotoxic effects in several patients [185].

Moreover, mitochondrial dysfunction is associated with impaired homocysteine metabolism, which leads to aging tissue degeneration [186]. Therefore, elevated plasma homocysteine levels are typical in AD patients in a moderate phase compared to AD patients in the initial and control groups. A polyphenol-rich antioxidant drink decreased plasma total homocysteine levels in AD patients, especially in the moderate phase [187]. The flavonoid-rich Ginkgo biloba extract(EGb 761) improved cognition, daily living, and social behavior in patients with uncomplicated ADor multi-infarct dementia—which are both associated with mitochondrial impairments [188]. Furthermore, the administration of EGCG in patients delayed the progression of multiple systems atrophy-associated disabilities |189].

Although beneficial effects of flavonoids were observed in the mentioned clinical studies, detailed mechanisms concerning mitochondrial impairments were not evaluated. Therefore, current clinical research indicates significant positive effects of flavonoids on neurodegenerative diseases, but the direct effects of flavonoids on mitochondrial function remain unclarified. Table 2 provides a detailed overview of the discussed clinical studies on the role of flavonoids in the etiopathology of mitochondriopathies, including cancer, CVDs, and neurodegenerative disorders.

5. Conclusions

Recent progress in 3P medicine demonstrates that patient stratification and individualized patient profiling are instrumental for cost-effective targeted prevention and treatments tailored to the person [4,5,7,9]. Individualized evaluation of the mitochondrial impairments [190,191] is essential for the risk assessment related to mitochondriopathies and associated pathologies, including but not restricted to cancer, CVDs, and neurodegenerative disorders [192-194]. Targeting mitochondrial homeostasis is a promising innovation in the overall therapeutic strategy.

The treatment and prevention of diseases in patients with mitochondriopathies have attracted a lot of attention in current research, novel therapeutic strategies. Contextually, flavonoids, naturally occurring polyphenolic compounds are of particular interest exerting significant health benefits in primary, secondary, and tertiary care protecting against stress overload, genotoxicity, mitochondrial dysfunction, and associated pathologies [195-199].

Both preclinical and clinical studies demonstrate flavonoids as highly protective agents reducing mitochondrial impairments and mitigating risks of associated pathologies. To improve individual outcomes and increase cost-efficacy, the 3 PM approach is strongly recommended to implement these benefits in healthcare providing new opportunities for prevention and treatment of stress-related disorders, oncology, cardiology, and neurology, amongst others [4,5,7,9,200,201].