Mitochondria are complex and highly dynamic organelles that are pivotal to a plethora of vital cellular functions. Besides their long-known role in bioenergetics, mitochondria are now recognized as critical signaling and metabolic hubs that are central to cellular physiology. In addition to ATP, mitochondria generate a variety of essential cofactors such as heme and iron-sulfur clusters and various metabolic precursors for lipids, proteins, and nucleic acids. Furthermore, mitochondria play an important role in regulating ion homeostasis and producing metabolic byproducts such as reactive oxygen species. The latter two functions are intertwined with inter-organellar communication and cellular signaling.
Given the paramount physiological significance of mitochondria, it is not surprising that progressive mitochondrial dysfunction and failing mitochondrial protein, redox, and metabolic homeostasis – hereinafter referred to as mitochondrial fidelity – have emerged as central factors in age-related diseases such as cardiovascular disorders, neurodegeneration, hearing and vision loss, and cognitive decline. Key challenges for mitochondrial wellbeing include: (i) the organelle’s complex protein environment, which is constantly challenged by substantial amounts of aberrant mitochondrial proteins synthesized by cells; (ii) oxygen radicals generated as a byproduct of mitochondrial respiration; and (iii) inherently reactive cofactors and metabolites produced and utilized by the organelle. The mitochondria and its complex homeostasis network involve multiple highly conserved dynamic processes and pathways that adapt to homeostatic challenges and change over time. These mechanisms are at the forefront of safeguarding mitochondrial functions and integrity under normal and stress conditions. The multifaceted biological roles of these mechanisms are highly relevant to both functional integrity of mitochondria and normal cellular physiology. As such, a deeper understanding of the mechanisms behind mitochondrial fidelity will further elucidate their diverse biological roles in normal and disease states.
This Special Issue of Mitochondrion features invited reviews on various aspects of mitochondrial homeostasis. The review by Ott and colleagues (Vazquez-Calvo et al., 2020) provides a general overview of molecular quality control mechanisms in different mitochondrial sub-compartments focusing on the principal components of these mechanisms. Additionally, they highlight recent developments in understanding the mechanisms that mediate mitochondrial protein homeostasis. The article by Barros and McStay (2020) reviews the current state of knowledge on the biogenesis of mitochondrial respiratory complexes and discusses this highly regulated process in the context of inner mitochondrial membrane (IM) proteostasis and related human diseases. Coyne and Chen (2019) further expand on the topic of IM protein homeostasis by focusing on the ATP/ADP exchanger and its role in IM proteostasic stress. They also discuss a recently identified IM stress response mechanism designated mitochondrial precursor overaccumulation stress, mPOS. The review by Steele and Glynn (2019) summarizes recent advances in the mechanistic understanding of mitochondrial AAA+ proteases – critical fidelity factors that use energy from ATP hydrolysis to destabilize and degrade proteins on both sides of the IM.
On a related tune, Fresenius and Wohlever (2019) review the current state of knowledge about the proteostasis network in the outer mitochondrial membrane (OM). In this context, they focus on the OM-residing AAA+ ATPase Msp1, which has emerged as a key regulator of protein homeostasis in this mitochondrial sub-compartment. The review article by Venkatesh and Suzuki (2019) focuses on mitochondrial matrix and discusses multifaceted roles of LonP1 AAA+ protease in maintaining protein and metabolic homeostasis in this subcellular compartment. In addition, they highlight emerging roles of LonP1 in responding to oncogenic and cardiac stress in humans. Finally, Carla Garza-Lombo and Rodrigo Franco (2020) provide an overview of yet another mitochondrial quality control process – selective degradation of damaged mitochondria through autophagy, commonly known as mitophagy. These authors review the molecular mechanisms that govern this critical homeostatic mechanism and discuss their relationship with mitochondrial redox signaling and oxidative stress.
Collectively, this Special Issue offers a compendium of review articles that cover several facets of the remarkably sophisticated process of mitochondrial fidelity. It summarizes recent advances in understanding of the quality control mechanisms that mediate fidelity and dynamics of the mitochondrial population in the cell. As these diverse, but highly intertwined mechanisms have emerged as prospective therapeutic targets in numerous mitochondria-linked disorders, better mechanistic understanding thereof may hold the key to treating or preventing these devastating maladies.