Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity

Abstract

Heat-shock response is an adaptive response to proteotoxic stresses including heat shock, and is regulated by heat-shock factor 1 (HSF1) in mammals. Proteotoxic stresses challenge all subcellular compartments including the mitochondria. Therefore, there must be close connections between mitochondrial signals and the activity of HSF1. Here, we show that heat shock triggers nuclear translocation of mitochondrial SSBP1, which is involved in replication of mitochondrial DNA, in a manner dependent on the mitochondrial permeability transition pore ANT–VDAC1 complex and direct interaction with HSF1. HSF1 recruits SSBP1 to the promoters of genes encoding cytoplasmic/nuclear and mitochondrial chaperones. HSF1–SSBP1 complex then enhances their induction by facilitating the recruitment of a chromatin-remodelling factor BRG1, and supports cell survival and the maintenance of mitochondrial membrane potential against proteotoxic stresses. These results suggest that the nuclear translocation of mitochondrial SSBP1 is required for the regulation of cytoplasmic/nuclear and mitochondrial proteostasis against proteotoxic stresses.

HSF1 is required for induction of mitochondrial chaperones during the mitochondrial unfolded protein response

“…In SSBP1‐knockdown cells, the expression of HSP70 mRNA was partially increased during the same treatment (Fig. 2B–D, gray bars), like during treatment with heat shock [18]. In marked contrast, HSP60 mRNA expression was not increased at all in SSBP1‐knockdown cells during treatment with GTPP or CDDO.…”

“…However, HSF1 was not thought to be involved in the upregulation of HSP60 and HSP10 during the UPR mt , because HSP70 was not upregulated simultaneously [6–7,16]. Recently, it was suggested that HSF1 in complex with a coactivator, mitochondrial single‐stranded DNA binding protein 1 (SSBP1), regulates the expression of mitochondrial chaperones, including HSP60, HSP10, and mtHSP70, during heat shock [18]. Of note, not only HSF1 but also mitochondrial SSBP1 accumulates in the nucleus and binds to the promoters of these genes on heat shock conditions [18].…”

“…Recently, it was suggested that HSF1 in complex with a coactivator, mitochondrial single‐stranded DNA binding protein 1 (SSBP1), regulates the expression of mitochondrial chaperones, including HSP60, HSP10, and mtHSP70, during heat shock [18]. Of note, not only HSF1 but also mitochondrial SSBP1 accumulates in the nucleus and binds to the promoters of these genes on heat shock conditions [18]. Therefore, it should be determined whether HSF1 and SSBP1 play an indispensable role in the UPR mt .…”

Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduce mitochondrial ROS production

“…However, this possibility is difficult to assess because of the high cytosolic abundance of STAT3. Other mitochondrial proteins, including the pyruvate dehydrogenase complex and SSBP1, can translocate from the mitochondria to the nucleus to regulate transcription under stress conditions (66, 67). This mitochondrial retrograde signaling event occurs in Caenorhabditis elegans , where the protein ATFS-1 links coordinate mitochondrial and nuclear programs (62, 68, 69).…”

The guardian of the genome p53 regulates exercise‐induced mitochondrial plasticity beyond organelle biogenesis

“…98,99 Given that exercise-induced stresses such as heat shock and/or moderate levels of ROS disturb mitochondrial protein homeostasis (eg, protein folding), 100 these disruptions may also serve as a trigger for SSBP1 infiltration into the nucleus, where it has been shown to enhance the promoter activity of genes encoding for mitochondrial chaperones. 101 Thus, it is conceivable that under physiological conditions, p53 can only translocate to the mitochondria and promote its biogenesis once energy and oxidative homeostasis have been restored. This hypothesis may also reconcile the inverse relationship that exists between oxidative stress and mitochondrial protein import, 38,39 and provide a possible mechanism for the delayed (compared to myofibrillar) peak in mitochondrial protein synthesis that occurs 24 hours following exercise.…”