Cytosolic Quality Control of Mitochondrial Protein Precursors—The Early Stages of the Organelle Biogenesis

Abstract

With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.

The Role of Mitochondrial Quality Control in Cognitive Dysfunction in Diabetes

“…Numerous quality control mechanisms have evolved within mitochondria to maintain proper function basally and in response to stress, including proteostasis, biogenesis, dynamics, and mitophagy [34]. Mitochondrial protein import is controlled and occurs in their unfolded form through various translocases, which is supported by mitochondrial membrane potential [35,36]. Molecular chaperones and intramitochondrial proteases control the integrity and proper assembly of the imported proteins [37,38].…”

OMA1 protease eliminates arrested protein import intermediates upon depolarization of the inner mitochondrial membrane

“…Thus, protein translocation failure requires adequate quality control (QC) responses. Cellular responses to stress caused by disturbed protein import have primarily been defined in the yeast model (Lenkiewicz et al, 2022). Fusion proteins designed to stall during the import proved to be an effective discovery platform to characterize the molecular mechanisms that resolve translocation failure in yeast (Boos et al, 2019;Martensson et al, 2019;Weidberg and Amon, 2018).…”

Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases

“…Since mitochondria are essential for eukaryotic organisms, these organelles possess several quality control mechanisms for counteracting dysregulated mitochondrial activity. Among them, the cytosolic protein quality control system prevents abnormal polypeptides from entering the mitochondria during mitochondrial biogenesis [18]. Mitophagy removes parts or entire mitochondria in response to mitochondrial damage [19].…”

“…This leads to an increase in proteasomal activity that degrades mitochondrial precursors in the cytosol, contributing to a response known as the mitoprotein-induced stress response. The latter is dependent on heat shock transcription factor 1 (HSF1), which, under stress conditions, is released from chaperone complexes [18].…”