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.
Highlights
Mitochondria are cell organelles formed in the process of endosymbiosis about 1.5 billion years ago [1,2]
The diversity of the mitochondrial proteome is naturally duplicated by the diversity of the precursor proteins, their targeting signals, and pathways that support their import
The membrane-bound ribosomes are engaged in the process of cotranslational transport, in which protein synthesis is coupled with translocation into the endoplasmic reticulum (ER)
Summary
Mitochondria are cell organelles formed in the process of endosymbiosis about 1.5 billion years ago [1,2]. Mitochondrial proteins are synthesized in the form of precursors that require efficient targeting, translocation, and maturation pathways to reach their intended destination and function within the organelle [5,6]. The combined efforts of many laboratories have substantially advanced our knowledge about the cytosolic fates of mitochondrial precursor proteins. These new discoveries have highlighted the direct linkage between the early stages of mitochondrial protein biogenesis and cytosolic proteostasis. We highlight the emerging links with human disease and point out open questions that await future discoveries
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