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Li, N. Mitochondria. Encyclopedia. Available online: (accessed on 06 December 2023).
Li N. Mitochondria. Encyclopedia. Available at: Accessed December 06, 2023.
Li, Ning. "Mitochondria" Encyclopedia, (accessed December 06, 2023).
Li, N.(2021, January 12). Mitochondria. In Encyclopedia.
Li, Ning. "Mitochondria." Encyclopedia. Web. 12 January, 2021.

Mitochondria are energy-producing structures and the main site for aerobic respiration in cells, and are therefore called the “powerhouse of the cell”.

mitochondria natural products

1. The Role of Mitochondria in Cancer Cells

Mitochondria are associated with many diseases, such as Parkinson’s disease [1], diabetic nephropathy [2], acute kidney injury [3], and Down syndrome [4]. Mitochondria also play an important role for cell signaling, apoptosis regulation, and energy metabolism in drug-induced cancer cells death; therefore, they are considered a significant target in cancer chemotherapy [5]. Some scholars have reviewed the mitochondrion as a target of anticancer therapy over the years [6][7][8][9]. Moreover, modulation of mitochondrial-dependent pathways by natural compounds is diverse (Figure 1). However, few researchers have reviewed natural products that regulate mitochondrial pathway in cancers.

Figure 1. Modulation of mitochondrial-related cell death by natural products. Cell death associated with the activity of natural products includes apoptosis, mitophagy, mitochondrial dysfunction, etc. Apoptosis is regulated by the levels of Bcl-2 (B-cell lymphoma-2) family proteins, release of cytochrome c, and caspase activation. Mitophagy is the targeted phagocytosis and destruction of mitochondria by the autophagy machinery, and it is generally considered as the main mechanism of mitochondrial quality control. A decrease in energy production, an increase of reactive oxygen species (ROS) and permeability transition pore (PTP) opening can lead to mitochondrial dysfunction.

2. Mitochondrial Control of Apoptosis

Mitochondrial involvement is an important pathway in the process of apoptosis. The Bcl-2 protein family regulates apoptosis by controlling mitochondrial permeability. Anti-apoptotic proteins B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL) reside in the outer membrane of mitochondria and inhibit the release of cytochrome c. Pro-apoptotic proteins Bax, Bad, Bid, and Bim can reside in the cytoplasm, translocating to mitochondria after receiving a death signal, and promote cytochrome c release into the cytoplasm. Released cytochrome c binds to apoptotic protease activating factor-1 (Apaf-1) to form apoptosome, amplifying the apoptotic cascade [10][11][12].

Necrotic stimulation leads to increased mitochondrial Ca2+ uptake and ROS production. High levels of Ca2+ and ROS induce the opening of the Cyclophilin-D (Cyp-D) sensitive permeability transition pore (PTP), leading to matrix swelling and Ca2+ release. Swelling damages the outer membrane and releases Ca2+ activating proteases, phosphatases, and nucleases, leading to necrotic degradation [13].

Fission or fusion rates may change under different growth conditions, and result in an increase or decrease in the number of mitochondria. When mitochondria become damaged, their connectivity is reduced, and mitochondria become shorter and rounder. The change from highly branched to fragmented morphologies may be induced by altered fission or fusion rates. At the early stage of apoptosis, the transition from a mitochondrial network to vesicular punctiform mitochondria was detected [14]. Mitochondrial fragmentation occurs in parallel to the formation of apoptotic bodies, increasing the number of the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei and cleavage of the caspase substrate polymerase (PARP) [15].

3. Mitochondrial Control of Energy Metabolism

Mitochondria provide considerable flexibility for the growth and survival of tumor cells, and play a key role in harsh conditions, such as nutrient depletion and hypoxia. The rapid proliferation of cancer cells requires more mitochondria than normal cells. Therefore, the development of chemotherapeutic drugs for mitochondria is a breakthrough in the fight against cancer. Many scholars have clarified that the mechanical drive of mitochondrial respiration involves the tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation enzymes in the mitochondrial matrix that generate electron donors to fuel respiration and electron transport chain (ETC) complexes, and ATP synthase in the inner mitochondrial membrane (IMM) that carry out oxidative phosphorylation [16]. Some natural products inhibit electron transport chain complexes. Four such complexes are NADH-ubiquinone reductase(complex I), succinate-ubiquinone reductase (complex II), ubiquinol-cytochrome c reductase (complex III), and cytochrome c oxidase (complex IV) [17]. Complex V, which is called ATP synthase, together with the above four complexes, completes oxidative phosphorylation to produce ATP. Inhibition of mitochondrial ETC complex activity can lead to significant mitochondrial dysfunction.

Cardiolipin, which consists of two phosphatidyl residues linked by a glycerol bridge, is a unique phospholipid dimer in the inner mitochondrial membrane in all eukaryotes. Cardiolipins play an important role in preserving mitochondrial structure and function. They support membrane dynamics and stabilize the lateral organization of protein-rich membranes in mitochondria [18]. Cardiolipins are involved in mitochondrial cristae morphology and stability [19], mitochondrial quality control, and dynamics by fission and fusion [20][21] and mitophagy [22]. They can also serve as a binding platform to recruit apoptotic factors in the apoptotic process [23][24]. However, it is still not clear how these events are interconnected and cooperate. In addition, cardiolipins are very susceptible to damage from ROS because of their high content of unsaturated acyl chains. Thus, the stability and function of mitochondria can be impaired by the biophysical properties of the membranes that are altered [25].

In this paper, we attempt to summarize the mechanisms through which natural products exert anticancer effects, as published in the past five years, by using a structural classification, with emphasis on the molecular mechanisms of mitochondrial involvement. Through all the reports, we found that most natural products regulate a series of proteins, such as Bax, Bcl-2, and caspases-3 and -9. Moreover, inhibitors of electron transport chain complexes can also exert anticancer activity. Details can be found in Table 1.

Table 1. Natural products (1–81) regulated mitochondria by different mechanisms in cancer cells.

No. Isolated Compound Origin Cell Line Mechanism Reference
1 Ganoleuconin O Ganoderma leucocontextum Huh7.5 Fatty acid immobilization, loss of the mitochondrial lipid cardiolipin [19]
2 Lupeol Bombax ceiba SK-RC-45 Mitochondrial hyper fission [20]
3 Betulinic acid Betula alba HeLa Cardiolipin modification, ROS generation, Bad, caspase 9 [21][22]
4 Alisol B-23-acetate Alisma orientale A549, NCI-H292 ROS generation, Bcl-2↓, Bax↑, activation of caspase-3, -9, release of cytochrome c/AIF [23]
5 Genipin Gardenia jasminoides N18TG2 Activation of dicarboxylate carrier, decreased activity of UCP1, UCP3, and complex III of the respiratory chain, UCP2 inhibition [24]
6 Alternol Yew tree PC-3 Decrease of mitochondrial respiration, isocitric acid, fumaric acid and malic acid, ATP production [25][26]
7 Cyathin Q Cyathus africanus HCT116 Bcl-2↓, Bax↑, Bcl-xL↓, ROS generation, release of cytochrome c [27]
8 3α-hydroxy-19α-hydrogen-29-aldehyde-27-lupanoic acid Potentilla discolor HepG2 Bcl-2↓, Bax↑, release of cytochrome c [28]
9 Uvedafolin Smallanthus sonchifolius HeLa MMP loss, release of cytochrome c [29]
10 Heteronemin Hippospongia sp. Molt4 ROS generation [30]
11 Jatrogossone A Jatropha gossypiifolia KOPN-8 MMP loss, ROS generation [31]
12 Walsuronoid B Walsura robusta Bel-7402, HepG2 ROS generation, mitochondrial and lysosomal dysfunction [32]
13 Ferruginol Podocarpus ferruginea MDA-T32 ROS generation, MMP loss, Bcl-2↓ [33][34]
14 Lobocrassin B Lobophytum crassum CL1-5, H520,
Bcl-2↓, Bax↑, ROS generation, MMP loss, release of cytochrome c, activation of caspase-3 [35]
15 Aellinane Euphorbia aellenii Caov-4 Bcl-2↓, Bax↑, ROS generation, MMP loss [36]
16 Tingenin B Maytenus sp. MCF-7s Bcl-2↓, Bax↑, MMP loss [37]
17 3-O-trans-p-coumaroyl alphitolic acid Ziziphus jujuba PC-3 ROS generation [38]
18 Zerumbone Zingiber zerumbet PC-3, DU-145 Tubulin binding and crosstalk between endoplasmic reticulum stress and mitochondrial insult [39][40]
19 Isoquercitrin Hibiscus cannabinus MDA-MB-231 LSD1-induced mitochondrial-mediated apoptosis pathway [41][42]
20 Luteolin Cauliflower, peanut, and carrot SW1990 Inhibitor of Bcl-2, mitochondrial permeabilization [43]
21 Dihydromyricetin Ampelopsis grossedentata HepG2 Akt/Bad signal pathway, mitochondrial apoptotic pathway, Bax↑, Bad↑, inhibition of the phosphorylation of Bad at Ser136 and Ser112 [44][45]
22 Artonin E Artocarpus elasticus SKOV-3 Release of cytochrome c, Activation of caspases-3, -8, and -9, Bax↑, Bcl-2↓, HSP70↓, survivin↓ [46]
23 Myricetin Fruits and vegetables SNU-80 Bax/Bcl-2↑, release of AIF [47]
24 Xanthones Garcinia xanthochymus HepG2 Bax↑, Bcl-2↓, Bcl-xL↓, Mcl-1↓, and survivin↓ [48]
25 Cycloartobiloxanthone Artocarpus gomezianus H460 Bax↑, Bcl-2↓, Mcl-1↓ [49]
26 Paratocarpin E Euphorbia humifusa MCF-7 Bax↑, Bcl-2↓, release of cytochrome c [50]
27 Puerarin 6′’-O-xyloside Pueraria lobata SW480 Bax↑, Bad↑, Bcl-2↓, caspase-3 and -9 activation [51]
28 α-mangostin Cratoxylum arborescens HeLa ROS generation, MMP loss, release of cytochrome c [52]
29 Chrysin Honey and propolis Mitochondria isolated from
hepatocytes of HCC rats
ROS generation, MMP loss, release of cytochrome c, swelling in mitochondria [53][54]
30 Fisetin Strawberries, apples, grapes, onions, and cucumbers SCC-4 ROS generation, Ca2+ production, MMP loss, Bcl-2↓, Bax↑, Bid↑, release of cytochrome c, AIF, and Endo G [55][56]
31 Baicalein Scutellaria baicalensis, Scutellaria radix A2780 Combination therapy with baicalein and taxol had
much higher antitumor effects compared with the monotherapy. Release of cytochrome c, and caspase-3 and -9 activation
32 Alpinetin Zingiberaceous
A549 Bcl-2↓, Bax↑, Bcl-xL↓, XIAP↓, PI3K/Akt signaling pathway, sensitized drug-resistant lung cancer cells [59][60]
33 Chamaejasmin B Stellerachamaejasme KB, KBV200 Bcl-2↓, Bax↑, MMP loss, release of cytochrome c and AIF [61]
34 Mensacarcin Streptomyces bacteria SK-Mel-28, SK-Mel-5, HCT-116 Release of cytochrome c, energy production and mitochondrial function rapidly disturbed [62]
35 Gracillin Dioscorea gracillima H226B, H460 Targeting mitochondrial complex II, suppressing ATP synthesis, ROS generation [63]
36 Polyphyllin I Paris polyphylla MDA-MB-231 Mitochondrial translocation of DRP1, mitochondrial fission, release of cytochrome c, mitochondrial PTEN-induced kinase 1↑ [64][65]
37 Frondoside A Cucumaria frondosa CA46 Bcl-2↓, survivin↓, release of HtrA2/Omi and cytochrome c, ROS generation [66]
38 3β-O-α-l-
Clematis ganpiniana MCF-7, MDA-MB-231 Release of cytochrome c and Apaf-1, upregulation of caspase-9 and caspase-3 [67]
39 Sakuraso-saponin Aegiceras corniculatum LNcaP, 22RV-1, C4-2 Bcl-xL↓ [68][69]
40 Ginsenoside compound K Panax ginseng SK-N-BE(2), SH-SY5Y Bcl-2↓, Bcl-xL↓ [70]
41 Escin Aesculus hippocastanum 786-O, Caki-1 G2/M arrest and ROS-modulated mitochondrial pathways [71]
42 α-Hederin Hedera helix SW620 NF-κB signaling pathway, Bcl-2↓, Bax↑, release of cytochrome c [72][73]
43 Cathachunine Catharanthus roseus HL60 ROS-dependent mitochondria-mediated intrinsic pathway, Bcl-2/Bax↓, ROS generation, MMP loss, release of cytochrome c [74]
44 Berberine Rhizoma coptidis T98G, LN18 ERK1/2-mediated impairment of mitochondrial aerobic respiration [75][76]
45 Papuamine Haliclona sp. H1299 Intracellular ATP depleted by causing mitochondrial dysfunction, mitochondrial superoxide production [77]
46 Bis (2-ethyl hexyl) 1H-pyrrole-3, 4-dicarboxylate Tinospora cordifolia MDA-MB-231 ROS generation, increase in intracellular calcium, phosphorylation of p53, mitochondrial membrane depolarization, MPTP, and cardiolipin peroxidation, Bcl-2↓, Bax↑, release of cytochrome c, caspase activation, DNA fragmentation [78]
47 Unantimycin A Found in the fraction library of microbial metabolites Semi-intact cells with specific substrates for each complex of the mitochondrial electron
transport chain
Targeted inhibition of mitochondrial complex I [79]
48 NPL40330 Found in chemical library Semi-intact cells with specific substrates for each complex of the mitochondrial electron
transport chain
Targeted inhibition of mitochondrial complex III [80]
49 Boholamide A Marine mollusks U87MG Influx of Ca2+ [81]
50 Cernumidine Solanum cernuum T24 Cytotoxicity and chemosensitizing effect of cernumidine to cisplatin. Bcl-2↓, Bax↑, MMP loss [82]
51 Lycorine Amaryllidaceae plant family HepG2 mPTP opening, MMP loss, ATP depletion, release of Ca2+ and cytochrome c, caspase activation [83]
52 Lagunamides A Lyngbya majuscule A549 MMP loss, ROS generation [84]
53 Cordycepin Cordyceps OVCAR-3 Downregulation of mitochondrial function and limitation of energy production; metastasis and migration suppressed [85][86]
54 2,3-Dihydro-7-
Ferula ferulaeoides C6 MMP loss, Bcl-xL↓, Bcl-2↓, Bax↑, cleavage of Bid, FAS↑, FADD↑ [87]
55 Dentatin Clausena excavate HepG2 Bcl-xL↓, Bcl-2↓, Bax↑, release of cytochrome c [88][89]
56 Aesculetin Cortex Fraxini THP-1 Bcl-2↓, Bax↑ [90]
57 Quambalarine B Quambalaria cyanescens Jurkat E6.1 Inhibition of mitochondrial complex I and II, inhibition of mitochondrial respiration, metabolism reprogramming [91][92]
58 Plumbagin Plumbago zeylanica MG63 ROS generation, Bcl-2↓, Bax↑, Bcl-xL↓, and Bak↓, endoplasmic reticulum stress [93]
59 Shikonin Lithospermum erythrorhizon HGC-27 Bcl-2↓, Bax↑, survivin↓ [94]
60 2,7-dihydroxy-3-methylanthraquinone Hedyotis diffusa SGC-7901 Bcl-xl↓, Bcl-2↓, Bax↑, Bad↑, release of cytochrome c [95]
61 3-hydroxy-1,5,6-trimethoxy-2-methyl-9,10-anthraquinone Prismatomeris connate A549, H1299 Bcl-2↓, Mcl-1↓, Bax↑ [96]
62 Thymoquinone Nigella sativa T24, 253J Bcl-2↓, Bax↑, release of cytochrome c and AIF [97]
63 Methylsulfonylmethane Fruits and vegetables YD-38 Bcl-xL↓, Bcl-2↓, Bax↑, release of cytochrome c, MMP loss [98][99]
64 Parameritannin A-2 Urceola huaitingii HGC27 Enhanced doxorubicin-induced mitochondria-dependent apoptosis, inhibition of the PI3K/Akt, ERK1/2 and p38 pathways, Bcl-2↓, Bcl-xl↓, Bax↑, Bid↑, release of cytochrome c, caspase activation [100]
65 Resveratrol Polygonum cuspidatum,
Veratrum nigrum,
Cassia obtusifolia
H838, H520;
Enhanced antitumor activities of cisplatin;
Induced apoptosis
66 Oleuropein Olea europaea H1299 Bcl-2/Bax↓, release of cytochrome c, activation of caspase-3 [103][104]
67 Homoisoflavanone-1 Polygonatum odoratum A549 Mitochondria-caspase-dependent and ER stress pathways, Bcl-2/ Bak↓ [105]
68 Gallic acid Green tea,
red wine
H446 ROS-dependent mitochondrial apoptotic pathway [106]
69 Hierridin b Cyanobium sp. HT-29 Proteomics identified 21 differentially expressed proteins belonging to the categories protein
folding/synthesis and cell structure and reduced mitochondrial activity and as confirmed by morphological analysis of mitochondrial parameters
70 Deoxyarbutin Ecklonia cava B16F10 MMP loss, ATP depletion and ROS overload generation [109]
71 Magnolol Magnolia officinalis OS-RC-2, 786-O P53, Bcl-2/Bax↓, release of cytochrome c, caspase activation, ROS generation [110]
72 Oblongifolin C Garcinia yunnanensis QBC939 Mitochondrial dysfunction [111]
73 Amorfrutin C Glycyrrhiza foetida HT-29 mPTP opening, mitochondrial oxygen consumption and extracellular acidification increased [112]
74 Allyl isothiocyanate Cruciferous vegetables MCF-7, MDA-MB-231 ROS and Ca2+ production, MMP loss, release of cytochrome c, AIF, and Endo G, Bcl-2↓, Bax↑ [113][114]
75 α-conidendrin Taxus yunnanensis MCF-7 and MDA-MB-231 ROS generation, p53↑, Bax↑, Bcl-2↓, MMP loss, release of cytochrome c, activation of caspases-3 and -9 [115]
76 Dehydrobruceine B Brucea javanica A549, NCI-H292 MMP loss, release of cytochrome c, cleavage of caspase-9, caspase-3, and poly (ADP-ribose) polymerase (PARP) [116]
77 Frugoside Calotropis procera M14, A375 ROS generation [117][118]
78 Methyl caffeate Solanum torvum MCF-7 Bcl-2↓, Bax↑, Bid↑, p53↑, cleavage of caspase-3 and PARP, release of cytochrome c [119]
79 Tetrahydrocurcumin Curcuma longa MCF-7 ROS generation, Bcl-2↓, PARP↓, Bax↑, release of cytochrome c, MMP loss [120]
80 Phloretin Apple tree leaves and Manchurian apricot EC-109 Bcl-2↓, Bax↑ [121]
81 Sesamol Sesame seeds HepG2 Bcl-2↓, Bax↑, MMP loss, H2O2 production, PI3K Class III/Belin-1 pathway [122]


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