RESUMO
The mitochondrial permeability transition pore (mPTP) or mitochondrial megachannel is arguably one of the most mysterious phenomena in biology today. mPTP has been at the center of ongoing extensive scientific research for the last several decades. In this review we will discuss recent advances in the field that enhance our understanding of the molecular composition of mPTP, its regulatory mechanisms and its pathophysiological role. We will describe our recent findings on the role of ATP synthase c-subunit ring as a central player in mitochondrial permeability transition and as an important metabolic regulator during development and in degenerative diseases.
Assuntos
Mitocôndrias , ATPases Mitocondriais Próton-Translocadoras , Subunidades Proteicas , Animais , Humanos , Suscetibilidade a Doenças , Metabolismo Energético , Mitocôndrias/metabolismo , Membranas Mitocondriais/química , Membranas Mitocondriais/metabolismo , ATPases Mitocondriais Próton-Translocadoras/química , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Modelos Moleculares , Plasticidade Neuronal , Neurônios/metabolismo , Permeabilidade , Conformação Proteica , Subunidades Proteicas/química , Subunidades Proteicas/metabolismoRESUMO
An instructive role for metabolism in embryonic patterning is emerging, although a role for mitochondria is poorly defined. We demonstrate that mitochondrial oxidative metabolism establishes the embryonic patterning center, the Spemann-Mangold Organizer, via hypoxia-inducible factor 1α (Hif-1α) in Xenopus. Hypoxia or decoupling ATP production from oxygen consumption expands the Organizer by activating Hif-1α. In addition, oxygen consumption is 20% higher in the Organizer than in the ventral mesoderm, indicating an elevation in mitochondrial respiration. To reconcile increased mitochondrial respiration with activation of Hif-1α, we discovered that the "free" c-subunit ring of the F1Fo ATP synthase creates an inner mitochondrial membrane leak, which decouples ATP production from respiration at the Organizer, driving Hif-1α activation there. Overexpression of either the c-subunit or Hif-1α is sufficient to induce Organizer cell fates even when ß-catenin is inhibited. We propose that mitochondrial leak metabolism could be a general mechanism for activating Hif-1α and Wnt signaling.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Mitocôndrias , Organizadores Embrionários , Animais , Trifosfato de Adenosina/metabolismo , Hipóxia , Mitocôndrias/metabolismo , Organizadores Embrionários/metabolismo , Xenopus laevisRESUMO
The mitochondrial F1Fo ATP synthase is one of the most abundant proteins of the mitochondrial inner membrane, which catalyzes the final step of oxidative phosphorylation to synthesize ATP from ADP and Pi. ATP synthase uses the electrochemical gradient of protons (ΔµH+) across the mitochondrial inner membrane to synthesize ATP. Under certain pathophysiological conditions, ATP synthase can run in reverse to hydrolyze ATP and build the necessary ΔµH+ across the mitochondrial inner membrane. Tight coupling between these two processes, proton translocation and ATP synthesis, is achieved by the unique rotational mechanism of ATP synthase and is necessary for efficient cellular metabolism and cell survival. The uncoupling of these processes, dissipation of mitochondrial inner membrane potential, elevated levels of ROS, low matrix content of ATP in combination with other cellular malfunction trigger the opening of the mitochondrial permeability transition pore in the mitochondrial inner membrane. In this review we will discuss the new role of ATP synthase beyond oxidative phosphorylation. We will highlight its function as a unique regulator of cell life and death and as a key target in mitochondria-mediated neurodegeneration and neuroprotection.
Assuntos
Doenças Neurodegenerativas/genética , Neuroproteção/fisiologia , ATPases Translocadoras de Prótons/fisiologia , Animais , Humanos , Doenças Neurodegenerativas/patologia , ATPases Translocadoras de Prótons/genéticaRESUMO
Mitochondrial ion channels are involved in numerous cellular processes. Membrane pores and transporters regulate the influx and efflux of calcium, sodium, potassium, zinc and determine the membrane compartmentalization of numerous cytosolic metabolites. The permeability of the inner membrane to ions and solutes helps determine the membrane potential of the inner membrane, but the permeability of the outer membrane, controlled in part by VDAC and the BCL-2 family proteins, regulates the release of important signaling molecules that determine the onset of programmed cell death. BCL-2 family proteins have properties of ion channels and perform specialized physiological functions, for example, regulating the strength and pattern of synaptic transmission, in addition to their well known role in cell death. The ion channels of the inner and outer membranes may come together in a complex of proteins during programmed cell death, particularly during neuronal ischemia, where elevated levels of the divalents calcium and zinc activate inner membrane ion channel conductances. The variety of possible molecular participants within the ion channel complex may be matched only by the variety of different types of programmed cell death.