The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic.
In addition to their well-known critical role in energy metabolism, mitochondria are now recognized as the location where various catabolic and anabolic processes, calcium fluxes, various oxygen-nitrogen reactive species, and other signal transduction pathways interact to maintain cell homeostasis and to mediate cellular responses to different stimuli. It is important to consider how pharmacological agents affect mitochondrial biochemistry, not only because of toxicological concerns but also because of potential therapeutic applications. Several potential targets could be envisaged at the mitochondrial level that may underlie the toxic effects of some drugs. Recently, antiviral nucleoside analogs have displayed mitochondrial toxicity through the inhibition of DNA polymerase-gamma (pol-gamma). Other drugs that target different components of mitochondrial channels can disrupt ion homeostasis or interfere with the mitochondrial permeability transition pore. Many known inhibitors of the mitochondrial electron transfer chain act by interfering with one or more of the respiratory chain complexes. Nonsteroidal anti-inflammatory drugs (NSAIDs), for example, may behave as oxidative phosphorylation uncouplers. The mitochondrial toxicity of other drugs seems to depend on free radical production, although the mechanisms have not yet been clarified. Meanwhile, drugs targeting mitochondria have been used to treat mitochondrial dysfunctions. Importantly, drugs that target the mitochondria of cancer cells have been developed recently; such drugs can trigger apoptosis or necrosis of the cancer cells. Thus the aim of this review is to highlight the role of mitochondria in pharmacotoxicology, and to describe whenever possible the main molecular mechanisms underlying unwanted and/or therapeutic effects.
Scatena
Roberto
R
Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy. r.scatena@rm.unicatt.it
Bottoni
Patrizia
P
Botta
Giorgia
G
Martorana
Giuseppe E
GE
Giardina
Bruno
B
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014116:Toxicology / Q000639:trends*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D000975:Antioxidants; D000998:Antiviral Agents; D002317:Cardiovascular Agents; D004272:DNA, Mitochondrial; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species