*Review* **Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration**

**Hope I. Needs 1 , Margherita Protasoni 2 , Jeremy M. Henley 1,3 , Julien Prudent 2 , Ian Collinson 1, \* and Gonçalo C. Pereira 2, \***


**Abstract:** The fact that >99% of mitochondrial proteins are encoded by the nuclear genome and synthesised in the cytosol renders the process of mitochondrial protein import fundamental for normal organelle physiology. In addition to this, the nuclear genome comprises most of the proteins required for respiratory complex assembly and function. This means that without fully functional protein import, mitochondrial respiration will be defective, and the major cellular ATP source depleted. When mitochondrial protein import is impaired, a number of stress response pathways are activated in order to overcome the dysfunction and restore mitochondrial and cellular proteostasis. However, prolonged impaired mitochondrial protein import and subsequent defective respiratory chain function contributes to a number of diseases including primary mitochondrial diseases and neurodegeneration. This review focuses on how the processes of mitochondrial protein translocation and respiratory complex assembly and function are interlinked, how they are regulated, and their importance in health and disease.

**Keywords:** protein import; mitochondrial dysfunction; respiratory complex assembly; supercomplexes; neurodegeneration; mitochondrial proteostasis

#### **1. Introduction**

Mitochondria provide the main source of cellular energy in the form of ATP. This is particularly important in high energy consuming cells such as cardiac and muscle cells as well as in neurons. On top of this vital role in ATP synthesis, mitochondria have a plethora of other roles, including regulation of cellular metabolism, calcium storage and signalling, reactive oxygen species (ROS) signalling, damage-associated molecular patterns (DAMPs) production in inflammation and immunity, and programmed cell death [1]. The presence of key enzymes and proteins in different submitochondrial compartments is indispensable for these roles. Consequently, protein translocation becomes a fundamental process for efficient mitochondrial physiology. Due to their diverse proteome, mitochondria have distinct import pathways, which must be fully operational to maintain a healthy organelle [2]. The first section of this review will cover how cytoplasmic translated proteins are imported into mitochondria, as well as how mitochondrial-encoded proteins are translocated from the matrix to the inner mitochondrial membrane (IMM). We then explore the special case of respiratory complexes, which are multimeric proteins assembled from subunits encoded by both the nuclear and mitochondrial genomes to highlight the importance of the import machineries.

**Citation:** Needs, H.I.; Protasoni, M.; Henley, J.M.; Prudent, J.; Collinson, I.; Pereira, G.C. Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration. *Life* **2021**, *11*, 432. https://doi.org/ 10.3390/life11050432

Academic Editors: Giorgio Lenaz and Salvatore Nesci

Received: 25 March 2021 Accepted: 2 May 2021 Published: 11 May 2021

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Due to the fundamental importance of mitochondrial homeostasis for the regulation of multiple central processes and pathways, it is not surprising that mitochondrial defects, and more specifically mitochondrial import defects, have been implicated in several diseases [3]. These include most neurodegenerative diseases [4], as well as mitochondrial diseases associated with deficiencies of the respiratory complexes due to mutations affecting the import machineries [5]. These will be discussed later, followed by a discussion of the recent advances therein and with respect to the most common mitochondrial stress response and proteostatic pathways thought to counteract import dysfunction.
