LAUSR

Mitochondria are dynamic, double-membrane-bound organelle of eukaryotic cells that have evolved to function in a wide range of cellular processes. They are responsible for oxidative phosphorylation (OXPHOS), producing energy and metabolites, regulating apoptosis and maintaining cell viability. To properly perform these functions, mitochondria depend on hundreds of proteins which are encoded in the nucleus, synthesized in the cytosol, and imported into the organelle. The transport of mitochondrial preproteins is mainly mediated by the translocase of the outer mitochondrial membrane and the translocase of the inner mitochondrial membrane [1]. Given the dependence of mitochondrial function on cytosolic synthesized proteins, maintaining efficient mitochondrial protein import is indispensable for cellular and organismal health. Therefore, it is not surprising that some sophisticated protective responses must exist to defend against deficient mitochondrial protein import in cells. Recently, a few mitochondria-to-nucleus signaling pathways were uncovered, including mitochondrial unfolded protein response (mtUPR) [2], unfolded protein response activated by mistargeting of proteins (UPRam) [3], and mitochondrial precursor overaccumulation stress (mPOS) [4]. In Caenorhabditis elegans, mtUPR is activated by the accumulation of unfolded protein within the mitochondrial matrix. As a result, mtUPR induces initiation of a nuclear encoded stress program including the transcriptional activation of mitochondrial stress proteins. mtUPR has been shown to play an important role in the mitochondrial protein quality control system [2,5]. UPRam was identified as a beneficial mechanism in yeast that protects cells against mitochondrial import defect and over-accumulation of mitochondrial precursor proteins in the cytosol. UPRam activation inhibits protein synthesis and triggers the proteasome for cellular protein clearance, which is governed by the Irc25–Poc4 complex [3]. A recent genetic study in yeast revealed a novel protective mechanism named mPOS against mitochondrial protein import deficiency. mPOS is a novel pathway of proteostatic stress-mediated cell death due to mitochondrial dysfunction. mPOS is triggered by mitochondrial damage and the aberrant accumulation of mitochondrial precursors in the cytosol. Consequently, mPOS reduces the translation of unimported proteins via upregulating ribosome-associated proteins including Gis2 and Nog2 [4]. Recently, mitoCPR was found in budding yeast. mitoCPR is a novel cellular response to defective mitochondrial protein import that protects mitochondrial functions [6]. All the above pathways provide a nuclear response to counteract the adverse effects of compromised mitochondrial functions (Table 1). MitoCPR is known as mitochondrial compromised protein import response [6]. Upon mitochondrial import stress, mitoCPR is triggered to restore mitochondrial import and plays a critical role in maintaining mitochondria functions. This protective process is mediated by the activation of the transcription factor, PDR3 as well as its downstream transcriptional effector, Cis1. Cis1 recruits the adenosine triphosphatase Msp1 to import channels on the mitochondrial outer membrane through binding to the translocase receptor Tom70. These proteins facilitate the removal and proteasomal degradation of unimported precursors located on the mitochondrial surface and translocase. This discovery reveals that mitoCPR serves as a novel beneficial pathway to keep mitochondrial protein homeostasis and mitochondrial functions during mitochondrial import stress. The identification of mitoCPR widens the mitochondria responses against accumulation of mitochondrial precursor proteins outside the organelle and further highlights the central role of mitochondrial import in mitochondrial functions. Multiple lines of evidence indicate a causative role of mitochondrial import defects in mitochondrial dysfunction and pathologies. Devi et al. [7] suggested that the accumulation of amyloid precursor protein (APP) inside the mitochondrial import channels, is a driving force for mitochondrial dysfunction and contributes to the pathology of Alzheimer’s disease (AD). The cell adhesion molecule L1 is an important regulator in the nervous system under physiological conditions. L1 cleavage product, L1-70, was shown to be imported from the cytoplasm into mitochondria and to be important for mitochondrial functions. Blocking the mitochondrial import of L1-70,