Abstract
Cells must adjust their redox state to an ever-changing environment that could otherwise result in compromised homeostasis. An obvious way to adapt to changing redox conditions depends on cysteine post-translational modifications (PTMs) to adapt conformation, localization, interactions and catalytic activation of proteins. Such PTMs should occur preferentially in the proximity of oxidative stress sources. A particular concentration of these sources is found near membranes where the endoplasmic reticulum (ER) and the mitochondria interact on domains called MERCs (Mitochondria-Endoplasmic Reticulum Contacts). Here, fine inter-organelle communication controls metabolic homeostasis. MERCs achieve this goal through fluxes of Ca2+ ions and inter-organellar lipid exchange. Reactive oxygen species (ROS) that cause PTMs of mitochondria-associated membrane (MAM) proteins determine these intertwined MERC functions. Chronic changes of the pattern of these PTMs not only control physiological processes such as the circadian clock but could also lead to or worsen many human disorders such as cancer and neurodegenerative diseases.
Highlights
Interactions between mitochondria and the Endoplasmic Reticulum (ER) were discovered in 1952 using electron microscopy of rat liver, where contacts between these two organelles depend on the nutritional status of the animal (Bernhard et al, 1952)
Less is known about links between the intermembrane space (IMS) folding environment and lipid homeostasis, but the generation of oxidized sterols leads to the recruitment of the ubiquitin proteasome system to remove the mitochondrial outer mitochondrial membrane (OMM) protein import machinery in yeast, suggesting this compartment could be affected in similar ways to the endoplasmic reticulum (ER) folding environment (Nielson et al, 2017)
Under conditions when the cyclic ER-mitochondria Ca2þ flux exceeds the normal mitochondrial buffering capacity, the ER can contribute to the triggering of cell death, using Ca2þ as a messenger (Pinton et al, 2008). Another example how MERCs mechanistically connect Reactive oxygen species (ROS) and Ca2þ signaling is based on uncoupling protein 3 (UCP3), which reduces ATP production and compromises sarco/endoplasmic reticulum Ca2þATPase (SERCA) pumping on the ER side of MERCs, highlighting additional connections between the ER and mitochondrial ATP (De Marchi et al, 2011)
Summary
Interactions between mitochondria and the Endoplasmic Reticulum (ER) were discovered in 1952 using electron microscopy of rat liver, where contacts between these two organelles depend on the nutritional status of the animal (Bernhard et al, 1952). Consistent with an important role of IMS redox conditions for their folding and functioning, many IMS proteins contain conserved cysteine residues, including mitochondrial Ca2þ-handling proteins (Vogtle et al, 2012; Hung et al, 2014).
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