Mitochondrial Quality Control Mechanisms and the PHB (Prohibitin) Complex

Abstract

Mitochondrial functions are essential for life, critical for development, maintenance of stem cells, adaptation to physiological changes, responses to stress, and aging. The complexity of mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expression, owing to the need of stoichiometrically assemble the oxidative phosphorylation (OXPHOS) system for ATP production. It requires, in addition, the import of a large number of proteins from the cytosol to keep optimal mitochondrial function and metabolism. Moreover, mitochondria require lipid supply for membrane biogenesis, while it is itself essential for the synthesis of membrane lipids. To achieve mitochondrial homeostasis, multiple mechanisms of quality control have evolved to ensure that mitochondrial function meets cell, tissue, and organismal demands. Herein, we give an overview of mitochondrial mechanisms that are activated in response to stress, including mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response (UPR^mt). We then discuss the role of these stress responses in aging, with particular focus on Caenorhabditis elegans. Finally, we review observations that point to the mitochondrial prohibitin (PHB) complex as a key player in mitochondrial homeostasis, being essential for mitochondrial biogenesis and degradation, and responding to mitochondrial stress. Understanding how mitochondria responds to stress and how such responses are regulated is pivotal to combat aging and disease.

Keywords: PHB complex; PHB-1; PHB-2; mitochondria; mitochondrial dynamics; mitochondrial unfolded protein response (UPRmt); mitophagy; prohibitins; quality control; stress response.

Figure 1

The mitochondrial unfolded protein responses, UPR^mt. In order to maintain mitochondrial proteostasis, the UPR^mt is activated and induces the expression of mitochondrial chaperones and proteases. In C. elegans, unfolded proteins within the mitochondrial matrix are cleaved by the mitochondrial protease, ClpP, and the resulting peptides are exported to the cytoplasm through the mitochondrial ATP-binding cassette (ABC) transporter, HAF-1. ATFS-1 presents a mitochondrial targeting sequence (MTS) and a nuclear localization signal (NLS). Under normal conditions ATFS-1 is imported to the mitochondria where it is degraded by the Lon protease. However, during stress ATFS-1 is translocated to the nucleus due to defective mitochondrial import and to the accumulation of peptides in the cytosol. Once in the nucleus, ATFS-1 together with DVE-1 and UBL- 5, induce the expression of genes involved in restoring mitochondrial homeostasis. In addition, mitochondrial stress causes changes in chromatin structure. In particular, mitochondrial stress induces the histone methyltransferase MET-2 and the nuclear co-factor LIN-65 for the di-methylation of the histone H3K9. Moreover, two demethylases, JMJD-1.2 and JMJD-3.1, have been shown necessary for the induction of the UPR^mt.

Figure 2

The role of the prohibitin (PHB) complex in mitochondrial homeostasis and turnover. Interactions involved in mitochondrial biogenesis are depicted in the left side, those involved in mitophagy in the right side. Both, physical and genetic interactions described for the PHB complex are depicted. PHB complex is involved in organization and stability of mitochondrial nucleoids together with ATAD3 in human cells. In yeast, as well as in mammals, prohibitins stabilize newly synthesized mitochondrial translation products of the electron transport chain (ETC), physically interacting with complex I and complex IV, acting as a holdase-unfoldase type of chaperone. In addition, PHB interacts with mitochondrial m-AAA proteases in yeast, suggesting a role for the PHB complex in protecting newly imported proteins from degradation by m-AAA protease. In a proteomic analysis, in mouse embryonic fibroblasts (MEF), PHB2 was found to interact with several proteins of the IMM involved in the import of nuclear-encoded proteins such as the translocase subunits TIM22 and TIM23, and components of the Pam import motor, Pam16p and DNAJC19/Pam18p, that helps mtHSP70 to pull polypeptides into the mitochondrial matrix. In synthetic lethal screens in yeast, PHB proteins have been genetically linked to MICOS and ERMES complexes. Therefore, PHB might belong to the ER-mitochondria organizing network linking the ER and the two mitochondrial membranes to maintain membrane architecture, mtDNA, as well as ion, protein and lipid homeostasis. Finally, binding of LC3 to PHB2 would ensure mitochondrial clearance by recruiting the autophagic machinery to the IMM following proteasome-mediated degradation of the OMM. TIM: translocase of the inner membrane; TOM: translocase of the outer membrane; OXPHOS: oxidative phosphorylation.