Alternative mitochondrial functions in cell physiopathology: beyond ATP production

It is well known that mitochondria are the main site for ATP generation within most tissues. However, mitochondria also participate in a surprising number of alternative activities, including intracellular Ca2+ regulation, thermogenesis and the control of apoptosis. In addition, mitochondria are the main cellular generators of reactive oxygen species, and may trigger necrotic cell death under conditions of oxidative stress. This review concentrates on these alternative mitochondrial functions, and their role in cell physiopathology.

mitochondrial permeability transition; uncoupling proteins; alternative oxidase; cardioprotection; free radicals; aging

Authorship

A.J. Kowaltowski

Universidade Estadual de Campinas, Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Campinas, SP, BrasilUniversidade Estadual de CampinasBrasilCampinas, SP, BrasilUniversidade Estadual de Campinas, Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Campinas, SP, Brasil

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Scheme 1
- Energy-dissipating pathways in mitochondria. The mitochondrial respiratory chain (resp. chain), located in the inner mitochondrial membrane, reduces oxygen to water to generate a proton gradient, essential for ATP synthesis. However, oxygen reduction may also be promoted by the plant mitochondrial alternative oxidase (alt. ox.) in a dissipating process which may not generate a proton gradient. The proton gradient is decreased by the activity of uncoupling proteins (UcP), which translocate fatty acid anions from the mitochondrial matrix to the cytoplasmic surface of the inner mitochondrial membrane. Fatty acid anions then combine with protons, and flip-flop electroneutrally across the lipid bilayer.

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Scheme 2
- Mitochondrial Ca²⁺ transport. Mitochondrial Ca²⁺ influx is mediated by the inner membrane uniporter or RaM and driven by the proton electrochemical potential. Ca²⁺ efflux is promoted by the Ca²⁺/2H⁺ and Ca²⁺/2Na⁺ (or Ca²⁺/3Na⁺) exchange. Na⁺ redistribution is maintained by the Na⁺/H⁺ antiporter. resp. chain, Respiratory chain.

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Scheme 3
- Mitochondrial generation of ROS. The respiratory chain (resp. chain) produces superoxide radicals (O₂^-·), which generate hydrogen peroxide (H₂O₂) and hydroxyl radicals (HO^·). Mitochondrial nitric oxide synthase (NOS) produces nitric oxide (NO^·), which combines with O₂^-· to generate peroxinitrite (ONOO^-). All these ROS may cause mitochondrial and cellular damage if present in excess. MPT, Mitochondrial permeability transition.

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Scheme 4
- Mitochondria can trigger cell death. Intact mitochondria contain cytochrome c (circles) and the apoptosis inducing factor (AIF, lines) in the intermembrane space. AIF is released from mitochondria after the latter undergo nonselective inner membrane permeabilization secondary to MPT, which results in mitochondrial swelling and outer membrane disruption. Cytochrome c may be released into the cytosol after MPT, upon Bax targeting to mitochondria or treatment with Ca²⁺. Once in the cytosol, both cytochrome c and AIF trigger apoptosis. MPT may also promote necrosis, since it results in mitochondrial dysfunction. MPT, Mitochondrial permeability transition.

Scheme 1 - Energy-dissipating pathways in mitochondria. The mitochondrial respiratory chain (resp. chain), located in the inner mitochondrial membrane, reduces oxygen to water to generate a proton gradient, essential for ATP synthesis. However, oxygen reduction may also be promoted by the plant mitochondrial alternative oxidase (alt. ox.) in a dissipating process which may not generate a proton gradient. The proton gradient is decreased by the activity of uncoupling proteins (UcP), which translocate fatty acid anions from the mitochondrial matrix to the cytoplasmic surface of the inner mitochondrial membrane. Fatty acid anions then combine with protons, and flip-flop electroneutrally across the lipid bilayer.

Scheme 2 - Mitochondrial Ca²⁺ transport. Mitochondrial Ca²⁺ influx is mediated by the inner membrane uniporter or RaM and driven by the proton electrochemical potential. Ca²⁺ efflux is promoted by the Ca²⁺/2H⁺ and Ca²⁺/2Na⁺ (or Ca²⁺/3Na⁺) exchange. Na⁺ redistribution is maintained by the Na⁺/H⁺ antiporter. resp. chain, Respiratory chain.

Scheme 3 - Mitochondrial generation of ROS. The respiratory chain (resp. chain) produces superoxide radicals (O₂^-·), which generate hydrogen peroxide (H₂O₂) and hydroxyl radicals (HO^·). Mitochondrial nitric oxide synthase (NOS) produces nitric oxide (NO^·), which combines with O₂^-· to generate peroxinitrite (ONOO^-). All these ROS may cause mitochondrial and cellular damage if present in excess. MPT, Mitochondrial permeability transition.

Scheme 4 - Mitochondria can trigger cell death. Intact mitochondria contain cytochrome c (circles) and the apoptosis inducing factor (AIF, lines) in the intermembrane space. AIF is released from mitochondria after the latter undergo nonselective inner membrane permeabilization secondary to MPT, which results in mitochondrial swelling and outer membrane disruption. Cytochrome c may be released into the cytosol after MPT, upon Bax targeting to mitochondria or treatment with Ca²⁺. Once in the cytosol, both cytochrome c and AIF trigger apoptosis. MPT may also promote necrosis, since it results in mitochondrial dysfunction. MPT, Mitochondrial permeability transition.

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Alternative mitochondrial functions in cell physiopathology: beyond ATP production

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