Development or disease: duality of the mitochondrial permeability transition pore

Abstract

Mitochondria is not only a dynamic organelle that produces ATP, but is also an important contributor to cell functions in both development and cell death processes. These paradoxical functions of mitochondria are partially regulated by the mitochondrial permeability transition pore (mPTP), a high-conductance channel that can induce loss of mitochondrial membrane potential, impairment of cellular calcium homeostasis, oxidative stress, and a decrease in ATP production upon pathological activation. Interestingly, despite their different etiologies, several neurodegenerative diseases and heart ischemic injuries share mitochondrial dysfunction as a common element. Generally, mitochondrial impairment is triggered by calcium deregulation that could lead to mPTP opening and cell death. Several studies have shown that opening of the mPTP not only induces mitochondrial damage and cell death, but is also a physiological mechanism involved in different cellular functions. The mPTP participates in regular calcium-release mechanisms that are required for proper metabolic regulation; it is hypothesized that the transient opening of this structure could be the principal mediator of cardiac and brain development. The mPTP also plays a role in protecting against different brain and cardiac disorders in the elderly population. Therefore, the aim of this work was to discuss different studies that show this controversial characteristic of the mPTP; although mPTP is normally associated with several pathological events, new critical findings suggest its importance in mitochondrial function and cell development.

Structure, function, and regulation of mitofusin‐2 in health and disease

“…However, the depletion of Mfn2 attenuated cardiac cell death in response to ischaemia-reperfusion injury and reduced the potential to undergo calcium-dependent mitochondrial permeability transition (MPT) (Papanicolaou et al, 2011). MPT is a tightly regulated process that is mediated by mitochondrial permeability transition pore (MPTP), a high-conductance, calcium-sensitive channel that induces mitochondrial depolarization and dysfunction upon opening (Haworth & Hunter, 1980;Perez & Quintanilla, 2017). MPTP is an important determinant of myocyte loss, especially during ischaemia and reperfusion injury (Di Lisa & Bernardi, 2006;Baines, 2009;Halestrap, 2009).…”

Mitochondrial dysfunction in endothelial cells induced by airborne fine particulate matter (<2.5 μm)

“…The ultrastructural damage of mitochondria in the ECs exposed to PM 2.5 was observed by transmission electron microscopy. As shown in (Kang et al, 2017;Pérez & Quintanilla, 2017). The ΔΨm loss in ECs (Figure 4) might be attributed to the direct interaction between PM 2.5 and the mitochondrion, leading to the physical damage in mitochondria and regulation of mPTPs to depolarize ΔΨm ( Figure 5).…”

“…The altered expressions of fission or fusion proteins further reflect PM 2.5 ‐induced mitochondrial damage. It was demonstrated that the induction of mitochondrial damage includes changes in ΔΨm and mPTP openings (Kang et al, ; Pérez & Quintanilla, ). The ΔΨm loss in ECs (Figure ) might be attributed to the direct interaction between PM 2.5 and the mitochondrion, leading to the physical damage in mitochondria and regulation of mPTPs to depolarize ΔΨm (Figure ).…”

MK2-deficient mice are bradycardic and display delayed hypertrophic remodelling in response to a chronic increase in afterload

“…Among mechanisms involved in mitochondrial pathogenesis is the opening of the mitochondrial permeability transition pore (MPTP), which results in uncoupling of the mitochondrial respiratory chain, impaired ATP synthesis, and eventually mitochondrial swelling and cell death (Kwong & Molkentin, 2015;Perez & Quintanilla, 2017). The exact molecular identity of this complex has not yet been well defined and is the subject of intense debate although the molecular structure of MPTP includes the volt-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT), and cyclophilin D, among other possible components that include the F1F0 ATP synthase for the pore-forming component (Bernardi & Di Lisa, 2015;Kwong & Molkentin, 2015).…”