Defective mitochondrial import as a challenge for cellular protein homeostasis

• Published in: FEBS letters 2023-06, Vol.597 (12), p.1555-1568
• Main Authors: Maruszczak, Klaudia K., Ayyamperumal, Selvaraj, Chacinska, Agnieszka
• Format: Article
• Language: English
• Subjects: Carrier Proteins - metabolism; cellular stress responses; Homeostasis; mitochondria; Mitochondria - metabolism; mitochondrial dysfunction; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; mitochondrial quality control; protein aggregates; protein homeostasis; Protein Transport - genetics; Proteostasis
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.14677

Mitochondria are organelles indispensable for the correct functioning of eukaryotic cells. Their significance for cellular homeostasis is manifested by the existence of complex quality control pathways that monitor organellar fitness. Mitochondrial biogenesis relies on the efficient import of mitochondrial precursor proteins, a large majority of which are encoded by nuclear DNA and synthesized in the cytosol. This creates a demand for highly specialized import routes that comprise cytosolic factors and organellar translocases. The passage of newly encoded mitochondrial precursor proteins through the cytosol to the translocase of the outer mitochondrial membrane (TOM) is under tight surveillance. As a result of mitochondrial import defects, mitochondrial precursor proteins accumulate in the cytosol or clog the TOM complex, which in turn stimulates cellular stress responses to minimize the consequences of these challenges. These responses are critical for maintaining protein homeostasis under conditions of mitochondrial stress. The present review summarizes recent advances in the field of mitochondrial protein import quality control and discusses the role of this quality control within the network of cellular mechanisms that maintain the cellular homeostasis of proteins. Most mitochondrial precursor proteins are translated on the cytosolic ribosomes and targeted to the mitochondrial translocase, the TOM complex. Any protein stalled during translocation at the TOM complex is recognized and extracted by specialized protein quality control mechanisms. Unimported mitochondrial proteins are either removed by the proteasome or form deposits in the cytosol.