Signaling pathway of mitochondrial stress

Signaling pathway of mitochondrial stress

Frontiers in Laboratory Medicine 1 (2017) 40–42 Contents lists available at ScienceDirect Frontiers in Laboratory Medicine journal homepage: www.kea...

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Frontiers in Laboratory Medicine 1 (2017) 40–42

Contents lists available at ScienceDirect

Frontiers in Laboratory Medicine journal homepage:;

Signaling pathway of mitochondrial stress Xue Fu, Hua Zhang ⇑ Guizhou Provincial People’s Hospital, Guizhou Province 550002, PR China

a r t i c l e

i n f o

Article history: Received 3 January 2017 Received in revised form 3 February 2017 Accepted 8 February 2017 Available online 24 March 2017 Keywords: Mitochondria Unfold protein response Retrograde response Import efficiency

a b s t r a c t Mitochondria, vital organelles, produce ATP efficiently for energy homeostasis via aerobic respiration and play a key role in tricarboxylic acid cycle, fatty acid oxidation, regulating of calcium homeostasis. Mitochondria are principal regulators of cell signaling via production of reactive oxygen species. Under various exogenous and/or endogenous stresses, mitochondria have the ability to adapt to changing environmental conditions, termed mitochondrial stress. Mitochondrial stress reconstructs mitochondrial homeostasis through integrated signaling termed the mitochondrial unfolded protein response (UPRmt). The mitochondrial UPRmt is a response of the cell to relieve mitochondrial damage and respond to proteotoxic stress specifically in mitochondria. Meanwhile, the mitochondrial UPRmt can sustain proteostasis and maintain overall cellular homeostasis. This review highlights the complex molecular mechanisms of the mitochondrial UPRmt. Ó 2017 Chinese Research Hospital Association. Production and hosting by Elsevier B.V. on behalf of KeAi. This is an open access article under the CC BY-NC-ND license (


Communication between mitochondria and nucleus

Mitochondria are double-membrane organelles of which structure is characterized by containing lipid bilayers in almost eukaryotic cells. The two main compartments of the mitochondria are separated by the inter mitochondrial membrane (IMM) and the outer mitochondrial membrane (OMM).The inter membrane space (IMS) intensely folded into cristae. Different cells harbor 10–1000 mitochondria. Mitochondria are composed of approximately 1100 proteins, which are encoded by genes located in both the mitochondrial genomes (mtDNA) and the nuclear genomes.1 Yet, most of the mitochondrial proteomes are encoded by the nuclear genomes, synthesized in the cytosol and imported into mitochondria. Mitochondria possess their own genome, which encodes 13 polypeptides of the electron transport chain (ETC), 22 tRNAs and 2 rRNAs required for their synthesis.2 Organismal lives in a sophisticated and unstable environment, and different adverse environmental conditions can induce varying degrees of mitochondrial stress.3,4 Different mitochondrial stress may cause mitochondrial dysfunction in different degrees. Mitochondrial dysfunction is one of the major pathological factors in neurological disorders.5 Thus, it’s meaningful to discuss the molecular mechanisms of the mitochondrial UPRmt.

In order to quickly adapt to changeable conditions, mitochondria evolve to well-integrated organelles communicated with other cell compartments. Under stress conditions, the signal conduction can be achieved from the misfolded or unfolded mitochondrial proteins within the matrix to the nucleus. Mitochondrial retrograde signaling or mitochondrion to nucleus communication has been discovered by Butow and Avadhani laboratories.6 Maintenance of protein homeostasis, the mitochondrial retrograde response increases nucleus encoded mitochondrial proteases and chaperones synthesis to facilitate protein folding or clearance of defective proteins in response to decreased mitochondrial activity, which is essential for organism functionality and survival. Recent works have not completely defined UPRmt extensively in mammals, but two potential signal transduction pathways may involve in retrograde response. One is mitochondrial membrane potential. The retrograde response can be triggered by low membrane potential, and blocked via restoring the membrane potential in rho and cox4 null yeast.7 The other one is cytosolic calcium accumulation.8 Assembling calcium within cytosolic causes activation of calcineurin and subsequently transcription factors.6 Under accumulation of misfolded or unfold proteins conditions, protein kinase R (PKR) is activated and elevates levels of phosphorylatedJNK9, which promotes the transcription factor c-Jun bind to the activation protein-1 (AP-1) element, then activates the transcription of CHOP.10,11 There exist two mitochondrial unfolded protein response elements (MURE1 and MURE2) adjacent to CHOP binding

⇑ Corresponding author. E-mail address: [email protected] (H. Zhang). 2542-3649/Ó 2017 Chinese Research Hospital Association. Production and hosting by Elsevier B.V. on behalf of KeAi. This is an open access article under the CC BY-NC-ND license (

X. Fu, H. Zhang / Frontiers in Laboratory Medicine 1 (2017) 40–42

site which present in promoters of UPRmt responsive genes.12,13 Interestingly, activation of UPRmt via JNK/c-jun pathway requires ClpP protease that could be a potential factor for inducing the UPRmt.9 During mitochondrial stress, cytosolic calcium homeostasis disruption activates the transcription factors of C/EBP homologous protein (CHOP), extracellular signal-regulated kinase 1 (ERK1), and nuclear factor kappa B (NF-jB).6 NF-jB activation is independently of the traditional repressor IjBa, but dependent on the inhibitor IjBb dephosphorylation, inducing NF-jB outward from the cytoplasm to the nucleus.14 Activation of these transcription factors turn on the expression of UPRmt target genes, including the mitochondrial chaperones HSP60, HSP10 and mtDnaJ encoded by the nuclear genome.13 Furthermore, upon mitochondrial stress additional proteases ClpP, Yme1L1, Lon and PMPCB, the import component TIMM17A and the enzymes NDUFB2, endonuclease G and thioredoxin 2 are all upregulated.12,15–17 There contain two particular mitochondrial chaperone systems that boost the newly synthesized or imported proteins folding in the matrix. mtHSP70, part of presequence translocase associated import-motor (PAM) complex, and polymer HSP60/HSP10 (chaperonin60/10) as main machinery, which is evolutionary conserved to restore mitochondrial proteostasis.18 HAF1 and UBL5/DVE-1 complex are two main downstream effectors of UPRmt in mitochondrial matrix. HAF1 acts as an ATP-binding cassette (ABC) peptide transporter located in mitochondrial inner membrane, which is essential for UPRmt signaling cascade.19 A small ubiquitin-like protein UBL5 and a transcription factor DVE-1 form a complex translocated into the nucleus that regulate the transcriptional activation of HSP60.20 Recent findings demonstrate a separate UPR other than the ‘classical’ UPRmt, which is independent on CHOP.21 The separate UPR is performed in two steps in the mitochondrial IMS. First of all, the 26S proteasome degrade the ubiquitinated unfolded or misfolded proteins. Then, the overloaded proteins are obliterated through the protease HTRA2.22 Aggregation IMS proteins evoke estrogen receptor a (ERa) via protein kinase B (AKT) phosphorylation.21 ERa activation boosts the transcription of the nuclear respiratory factor 1 (NRF1) and HTRA2 to maintain mitochondrial homeostasis. Recently, we were not able to confirm certain signaling pathway of UPRmt, even more signaling molecules should be identified.

Mitochondrial protein import efficiency Recent studies indicate that the mitochondrial protein import efficiency is a potentially valuable pathway to assess mitochondrial function.23 As a result of mitochondrial unique structure, the protein import encounters enormous challenges. More than 99% of the total mitochondrial protein is synthesized in the cytoplasm which is encoded by the nuclear genome.15 The synthesized protein traffic to mitochondria by signal sequences as precursors. Import into mitochondria requires the translocase of the outer mitochondrial membrane (TOM) and the inner mitochondrial membrane (TIM).18,24 The outer mitochondrial membrane (TOM) acts as entrance, then the translocase of the inner mitochondria membrane (TIM) targets precursor proteins to mitochondria lumen.25 Proteins translocated to the mitochondrial matrix have an amphipathic helix, termed N-terminal mitochondrial targeting sequence (MTS). Firstly, the MTS binds to the cytoplasm surface of the mitochondria by the outer mitochondrial membrane channel, subsequently cross the inner membrane and enter the matrix through the TIM23 complex. Once located in the matrix, with the assistance of mitochondria chaperones system including HSP60 and mtHSP70, the MTS is cleaved in the promotion of protein refolding or assembling in the mitochondria lumen.18 The activating Transcription Factor associated with Stress-1 (ATFS-1), which contains both nuclear localization sequence


(NLS) in the leucine zipper domain and N-terminal MTS, serves as a bridge between the mitochondria and nucleus in UPRmt signaling, and senses the import efficiency of mitochondria. Under basal condition, ATFS-1 is targeted to mitochondria and degraded by the Lon protease as an invalid regulatory mechanism.23 Upon mitochondrial stress, UPRmt signaling impairs mitochondrial import efficiency, part of ATFS-1 cannot be imported into mitochondria and assembles in the cytoplasm.19,23 Due to the NLS of ATFS-1, it can traffic to the nucleus to induce a protective transcriptional program to relieve the damage of mitochondrial stress. TIM-17 and TIM-23, two key elements of the TIM23 complex, are upregulated by ATFS-1, which are essential for the N-terminal MTS proteins imported to the mitochondrial matrix.18 As expected, ATFS-1 activated the expression of the mitochondrial chaperone and proteases genes to restore import efficiency and re-establish mitochondrial homeostasis.23 Recent findings have shown that any condition that disturbs import efficiency, such as deletions in mitochondrial ETC genes26, mitochondrial chaperone and protease inhibition12,23, cause ATFS-1 dependent UPRmt. These studies demonstrate that the UPRmt alters mitochondrial metabolism to protect mitochondrial homeostasis and cell survival during stress. Conclusions Complicated and changeable environment, and the external stress can perturb mitochondrial function, cells evolve multiple signaling pathways to adapt to protect mitochondria and maintain cellular homeostasis. The molecular mechanisms of mitochondrial stress signaling pathways are quite complex and have dual functions in cell survival and death. The mitochondrial unfolded protein response has been described, but the explicit mechanisms have only recently begun to be studied. Recent researches of the mitochondrial unfolded protein response determine that the retrograde response and mitochondrial protein import efficiency act as indicators of mitochondrial function. Here, we have depictive several mitochondrial signaling pathways that protect mitochondrial function and cell survival during mitochondrial stress. Meanwhile, we review the UPRmt mechanism of transcriptional activation to alleviate mitochondrial dysfunction during stress. Under mitochondrial stress, disruption or dysfunction of the mitochondria has been associated with several pathological conditions, including metabolic diseases, cancer and neurodegenerative diseases. In the future, it will play a pivotal role in determining whether the signaling pathways are protective against diseases during mitochondrial dysfunction. These studies are still in the early stages. Further clarification of the full complexity of the UPRmt pathway and its role in physiology and pathology will be a major goal for years to come.

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