Abstract
Mitochondrial permeability transition pore (PTP), a (patho)physiological phenomenon discovered over 40 years ago, is still not completely understood. PTP activation results in a formation of a nonspecific channel within the inner mitochondrial membrane with an exclusion size of 1.5 kDa. PTP openings can be transient and are thought to serve a physiological role to allow quick Ca2+ release and/or metabolite exchange between mitochondrial matrix and cytosol or long-lasting openings that are associated with pathological conditions. While matrix Ca2+ and oxidative stress are crucial in its activation, the consequence of prolonged PTP opening is dissipation of the inner mitochondrial membrane potential, cessation of ATP synthesis, bioenergetic crisis, and cell death—a primary characteristic of mitochondrial disorders. PTP involvement in mitochondrial and cellular demise in a variety of disease paradigms has been long appreciated, yet the exact molecular entity of the PTP and the development of potent and specific PTP inhibitors remain areas of active investigation. In this review, we will (i) summarize recent advances made in elucidating the molecular nature of the PTP focusing on evidence pointing to mitochondrial FoF1-ATP synthase, (ii) summarize studies aimed at discovering novel PTP inhibitors, and (iii) review data supporting compromised PTP activity in specific mitochondrial diseases.
Highlights
Situated in the cytoplasm of eukaryotic cells, mitochondria are essential for normal cell function
Studies in cybrid cell lines harboring mutations known to cause Leber’s hereditary optic neuropathy (LHON) revealed that these cells (i) are sensitized to Ca2+- or oxidative stress-triggered membrane depolarization and cell death compared to controls [75, 77] and (ii) their mitochondria depolarize if challenged with respiratory chain or ATP synthase inhibitors in a reactive oxygen species (ROS)- and Ca2+-dependent manner [78], effects that could be counteracted by CsA treatment
The molecular entity of the permeability transition pore (PTP) is the matter of active investigation, which favors ATP synthase as a prime suspect, yet recent studies suggest that other proteins, like ANT, might contribute
Summary
Situated in the cytoplasm of eukaryotic cells, mitochondria are essential for normal cell function These dynamic, double membrane structures gained considerable attention in recent years due to their role in Ca2+ homeostasis, interorganelle communication, cell proliferation, and senescence, as well as the orchestration of various signaling pathways some of which determine cell commitment to death or survival [1]. Most importantly, their vital function in cell physiology is by providing the cell with energy in the form of ATP through oxidative phosphorylation (OXPHOS). All of these features are consistent with impaired regulation of the mitochondrial permeability transition pore (PTP), a conserved physiological process in mitochondria of all eukaryotes
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