TABLE 1

Overview of example drugs with FDA black box warnings for cardiovascular, renal and hepatic toxicity^a

Drug class	Drug	Toxicity	Mitochondrial Toxic Effects	Reference
Alkylating agents	Cisplatin	Renal	Complex I and IV inhibition, declined MMP, low mtDNA, lower FAO, inhibition of protein synthesis	Miller et al., 2010; Pereira et al., 2009; Santos et al., 2007; Zsengellér et al., 2012
Alkylating agents	Ifosfamide	Renal	Complex I inhibition	Nissim et al., 2006
Anesthetic	Bupivacaine	Cardiovascular	OCR reduction, mitochondrial swelling	Hiller et al., 2013
Antiarrhythmic	Amiodarone	Cardiovascular	Complex I inhibition, reduction in ATP, OXPHOS uncoupling, MMP dissipation	Karkhanis et al., 2018
	Disopyramide	Cardiovascular	—
	Dofetilide	Cardiovascular	—
	Ibutilide	Cardiovascular	—
Anthracyclines	Daunorubicin	Cardiovascular	MMP dissipation, ROS elevation, lipid peroxidation, inhibition of topoisomerase II (mtDNA)	Bloom et al., 2016; Luo et al., 2009; Wu et al., 2014
	Doxorubicin	Cardiovascular/ Renal	Loss of cytochrome C, downregulation TCA protein expression, lipid peroxidation, decreased mtDNA content, oxidative stress	Benzer et al., 2018; Brandão et al., 2021; Gnanapragasam et al., 2007; Lahoti et al., 2012; Lebrecht et al., 2010; Oz et al., 2006; Pereira et al., 2016
	Epirubicin	Cardiovascular	Nitrosative stress	Guven et al., 2007
	Idarubicin	Cardiovascular	Mitochondrial swelling, inhibition of antioxidant enzymes, ROS elevation, lipid peroxidation, inhibition of topoisomerase II (mtDNA)	Bloom et al., 2016; Kalender et al., 2002
Antibiotics	Gentamicin	Renal	Decreased MMP, reduced mtDNA, ROS elevation, complex II inhibition	Chen et al., 2017b; Gai et al., 2020
	Isoniazid	Hepatic	ROS elevation through complex I–III inhibition, increased lipid peroxidation, dissipation MMP, mitochondrial swelling, cytochrome C release	Ahadpour et al., 2016
	Ketoconazole	Hepatic	Complex I–IV inhibition, ATP depletion, decreased mtDNA, decreased MMP, superoxide accumulation	Haegler et al., 2017; Rodriguez and Acosta, 1996
	Streptozocin	Hepatic	—
	Trovafloxacin	Hepatic	—
Anti-cancer	Arsenic trioxide	Cardiovascular	Structural mitochondrial damage, abnormal mPTP opening, ROS elevation, downregulation mitochondrial biogenesis	Zhang et al., 2018a
	Cetuximab	Cardiovascular	—
	Dacarbazine	Hepatic	—
	Denileukin diftitox	Cardiovascular	—
	Flutamide	Hepatic	MMP dissipation, ATP depletion, complex I inhibition	Ball et al., 2016; Coe et al., 2007; Fau et al., 1994; Zhang et al., 2018b
	Gemtuzumab	Hepatic	—
	Mitoxantrone	Cardiovascular	—
	Methotrexate	Hepatic	—
	Pentostatin	Hepatic	—
	Tamoxifen	Cardiovascular/ hepatic	OXPHOS uncoupling, inhibition of complex III and IV, inhibition FAO, mtDNA depletion	Gudbrandsen et al., 2006; Larosche et al., 2007; Lelliott et al., 2005; Satapathy et al., 2015; Tuquet et al., 2000
Antivirals	Abacavir	Hepatic	Inhibition of mtDNA polymerase gamma	Brinkman and Kakuda, 2000
	Didanosine	Hepatic	mtDNA depletion and inhibition of mtDNA polymerase gamma	Igoudjil et al., 2006; Mihajlovic and Vinken, 2022; Walker et al., 2004
	Emtricitabine	Hepatic	—
	Entecavir	Hepatic	—
	Emtricitabine	Hepatic	—
	Lamivudine	Hepatic	mtDNA depletion and inhibition of mtDNA polymerase gamma	Igoudjil et al., 2006
	Nevirapine	Hepatic	MMP dissipation	Paemanee et al., 2017
	Telbivudine	Hepatic	—
	Tipranavir	Hepatic	—
	Stavudine	Hepatic	mtDNA depletion and inhibition mtDNA polymerase gamma	Walker et al., 2004
	Zalcitabine	Hepatic	Depletion of mtDNA	Walker et al., 2004
	Zidovudine	Hepatic	Mitochondrial swelling, inhibition of complex II, MMP dissipation, loss of cytochrome C, ROS elevation, mtDNA depletion	Elimadi et al., 1997; Igoudjil et al., 2006; Lewis et al., 1994; Mihajlovic and Vinken, 2022; Scruggs and Dirks Naylor, 2008
Beta-blockers	Atenolol	Cardiovascular	Mitochondrial swelling, inhibition of complex II, MMP dissipation, loss of cytochrome C, ROS elevation	Seydi et al., 2020
CNS agents	Amphetamines	Cardiovascular	Impaired OXPHOS, ROS elevation	Chen et al., 2017a
	Atomoxetin	Cardiovascular	—
	Dantrolene	Hepatic	—
	Droperidol	Cardiovascular	—
	Felbamate	Hepatic	—
	Methamphetamine	Cardiovascular	—
	Naltrexone	Hepatic	—
	Nefazodone	Hepatic	Inhibition of complex I and IV, collapse mitochondrial membrane potential, imposed oxidative stress	Dykens et al., 2008
	Pergolide	Cardiovascular	—
	Valproic acid/ Divalproex sodium	Hepatic	mPTP opening, inhibition of FAO enzymes and sequestration of FAO cofactors	Aires et al., 2010; Li et al., 2015; Silva et al., 2008
Diabetes	Pioglitazone	Cardiovascular	Mitochondrial swelling, MMP dissipation, loss of cytochrome C, ROS elevation	Seydi et al., 2020
Diabetes	Rosiglitazone	Cardiovascular	Inhibition of complex I and IV, uncoupling OXPHOS, increase mitochondrial oxidative stress, impairment mitochondrial bioenergetics	He et al., 2014
Hypertension	Bosentan	Hepatic	—
Immunosuppressants	Cyclosporin A	Renal	Decreased MMP, ROS elevation, increased mitochondrial fission, liberation of cytochrome C	de Arriba et al., 2013
NtRTIs	Tenofovir	Hepatic/Renal	Inhibition of mtDNA polymerase gamma	Kohler et al., 2009
NSAIDs	Celecoxib	Cardiovascular	Mitochondrial swelling, inhibition of complex IV, reduction in ATP content, MMP dissipation, decreased antioxidant enzyme level, ROS elevation, lipid peroxidation	Atashbar et al., 2022; Salimi et al., 2019
	Diclofenac	Cardiovascular	Mitochondrial swelling, complex II and III inhibition, reduction in ATP content, OXPHOS uncoupling, MMP dissipation, decrease antioxidant enzyme level, ROS elevation, lipid peroxidation, inhibition of ANT	Brandolini et al., 2020; Ghosh et al., 2016a; Khezri et al., 2020; Moreno-Sánchez et al., 1999; Salimi et al., 2019; Thai et al., 2021
	Diflunisal	Cardiovascular	—
	Etodolac	Cardiovascular	—
	Fenoprofen	Cardiovascular	—
	Ibuprofen	Cardiovascular	OXPHOS uncoupling	Satapathy et al., 2015
	Indomethacin	Cardiovascular	Reduction in ATP content, OXHPOS uncoupling, MMP dissipation	Moreno-Sánchez et al., 1999
	Ketoprofen	Cardiovascular	—
	Mefenamic acid	Cardiovascular	Induction of mPTP opening	Olszewska and Szewczyk, 2013; Uyemura et al., 1997
	Meloxicam	Cardiovascular	Reduction in ATP content, OXHPOS uncoupling, MMP dissipation	Moreno-Sánchez et al., 1999
	Naproxen	Cardiovascular	Mitochondrial swelling, complex I and II inhibition, reduction in ATP content, MMP dissipation, decrease antioxidant enzyme level, ROS elevation, lipid peroxidation	Ghosh et al., 2016b; Salimi et al., 2019
	Nabumetone	Cardiovascular	—
	Oxaprozin	Cardiovascular	—
	Piroxicam	Cardiovascular	Reduction in ATP content, OXHPOS uncoupling, MMP dissipation	Moreno-Sánchez et al., 1999
	Salsalate	Cardiovascular	—
	Sulindac	Cardiovascular	Mitochondrial uncoupling, membrane dissipation, ATP depletion	Leite et al., 2006
	Tolmetin	Cardiovascular	—

ANT, adenine nucleotide translocase; CNS, central nervous system; FDA, Food and Drug Administration; FAO, fatty acid β-oxidation; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mtDNA, mitochondrial DNA; NSAID, nonsteroidal anti-inflammatory drug; NtRTI, nucleotide reverse transcriptase inhibitor; OCR, oxygen consumption rate.
^aDrugs for which the toxicity is related to mitochondrial liabilities are shown in bold. The reported toxic effects on mitochondrial function are indicated.