Revisiting trends on mitochondrial mega-channels for the import of proteins and nucleic acids

Abstract

The discovery of very large channels in the two membranes of mitochondria represented an astonishing finding and a turning point in the awareness of these conspicuous energy-generating organelles. Sizable channels are at the crossroads of important cellular pathways and mitochondrial functions like biogenesis, signaling, secretion, compartmentalization or apoptosis. The integrative approach that combines electrophysiological methods with biochemical and genetic alterations has been decisive to tackle the structure-function relationship of mitochondrial mega-channels. In this review we will give a short account of our joint effort to correlate the existence of large conductance channels in the two membranes of mitochondria with a precise function. In particular, we will focus on the import of proteins and nucleic acids. An analysis of the character of the aqueous pores through which these two types of macromolecules enter mitochondria has been attained, and an up-to date survey of the developments reached in these investigations will be presented. An overlook of the import pathways for proteins and nucleic acids into mitochondria will be outlined. Although this research area is rapidly developing, many issues remain shrouded in uncertainties. A special emphasis will be prone to the not yet entirely settled synergies between different protein translocases.

Mitochondrial Outer Membrane Channels: Emerging Diversity in Transport Processes

“…In yeast, two isoforms exists: the major form Por1 and the low abundant Por2 . In human mitochondria three VDAC isoforms are present . VDAC plays an important role for cellular energy metabolism by importing ADP and exporting ATP.…”

“…VDAC plays an important role for cellular energy metabolism by importing ADP and exporting ATP. In addition, the flux of NADH and anionic metabolites like malate, succinate and other molecules up to 5 kDa has been assumed to occur via the VDAC channel, while it remained unclear whether VDAC may be significantly permeable to cationic metabolites and ions . A few years ago three independent crystal and NMR structures show that mammalian VDAC1 forms a 19‐stranded β‐barrel with a small N‐terminal α‐helix that localizes inside the channel.…”

“…Due to the limited anion selectivity of VDAC one can expect that depending on the ionic milieu at the channel vestibule, cations may also be able to pass the VDAC channel . However, the characteristic fingerprint of an open VDAC channel has not been found in mitochondrial outer membrane vesicles or isolated mitochondria, indicating that VDAC channels in mitochondria are frequently in a closed state. Indeed, it has been shown that opening of the channel is modulated by different physiological stimuli .…”

“…The transport via the VDAC channel is driven by the concentration gradient across the outer membrane. Until a few years ago it was generally assumed that VDAC acts as a kind of “size exclusion filter,” allowing the unimpeded transport of molecules up to 5 kDa . In addition, during apoptosis a pore is formed in the outer membrane of mammalian mitochondria to release cytochrome c from the intermembrane space that in turn leads to activation of cytosolic caspases and eventually cell death.…”

Editorial note

“…Peixoto and collaborators presented their findings on the mechanisms of action of small molecule inhibitors of MAC (Peixoto et al 2015). A review by Martinez-Caballero describes import pathways important for biogenesis of mitochondrial proteins and the emerging pathways of DNA and RNA import (Campo et al 2016), while McStay reviews the mechanisms of turnover of such channels and transporters (McStay 2016). Finally, Elustondo and colleagues reviewed the mechanisms of mitochondrial calcium uptake (Elustondo et al 2016).…”