Signaling the mitochondrial unfolded protein response

Pellegrino, Mark W.; Nargund, Amrita M.; Haynes, Cole M.

doi:10.1016/j.bbamcr.2012.02.019

Cited by 310 publications

(296 citation statements)

References 102 publications

(149 reference statements)

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“…The UPR mt acts similarly to the UPR of the endoplasmic reticulum (19). While the UPR of the endoplasmic reticulum was the first to be identified, the activation of the UPR mt has only recently begun to be appreciated (20)(21)(22)(23)(24) and has yet to be elucidated. Moreover, its relation to cancer has not been established.…”

mentioning

confidence: 99%

SirT3 Regulates the Mitochondrial Unfolded Protein Response

Papa

Germain

2014

Molecular and Cellular Biology

242

213

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The mitochondria of cancer cells are characterized by elevated oxidative stress caused by reactive oxygen species (ROS). Such an elevation in ROS levels contributes to mitochondrial reprogramming and malignant transformation. However, high levels of ROS can cause irreversible damage to proteins, leading to their misfolding, mitochondrial stress, and ultimately cell death. Therefore, mechanisms to overcome mitochondrial stress are needed. The unfolded protein response (UPR) triggered by accumulation of misfolded proteins in the mitochondria (UPR mt ) has been reported recently. So far, the UPR mt has been reported to involve the activation of CHOP and estrogen receptor alpha (ER␣). The current study describes a novel role of the mitochondrial deacetylase SirT3 in the UPR mt . Our data reveal that SirT3 acts to orchestrate two pathways, the antioxidant machinery and mitophagy. Inhibition of SirT3 in cells undergoing proteotoxic stress severely impairs the mitochondrial network and results in cellular death. These observations suggest that SirT3 acts to sort moderately stressed from irreversibly damaged organelles. Since SirT3 is reported to act as a tumor suppressor during transformation, our findings reveal a dual role of SirT3. This novel role of SirT3 in established tumors represents an essential mechanism of adaptation of cancer cells to proteotoxic and mitochondrial stress. Mitochondrial reprogramming associated with elevated reactive oxygen species (ROS) levels is a hallmark of cancers. Altered mitochondrial metabolism and ROS, both required during oncogenic transformation (1-4), are regulated by the mitochondrial deacetylase SirT3 (5-7). Reduction in SirT3 levels and the resulting elevated ROS levels have been directly linked to the switch to glycolysis, known as the Warburg effect (8). While ROS are required for glucose metabolism and metastasis in triple-negative breast cancers (9), decreased SirT3 levels concomitant with high ROS levels are frequently observed in all breast cancers (8). Based on these findings, SirT3 is considered a tumor suppressor (5,8).SirT3 regulates the activity of magnesium superoxide dismutase (MnSOD), which detoxifies superoxide to hydrogen peroxide (5,7,(10)(11)(12)(13)(14). Moreover, SirT3 has been linked to augmented transcription of MnSOD and catalase, both known targets of the transcription factor FOXO3A (15). The SirT3-dependent deacetylation of FOXO3A promotes both its nuclear translocation and its transcriptional activity (16,17). Therefore, mechanistically, the reduction of SirT3 levels leads to an elevation in ROS levels by compromising the mitochondrial antioxidant machinery.Mitochondria are the main source of ROS production (18). However, they are also the main targets of oxidative stress. Excessive ROS induce oxidative damage to DNA, lipids, and proteins, leading to their misfolding and aggregation in the mitochondria. Upon accumulation of misfolded and aggregated proteins in the mitochondria, cells mount the unfolded protein response (UPR mt ), a mitochondrial-to nu...

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confidence: 99%

SirT3 Regulates the Mitochondrial Unfolded Protein Response

Papa

Germain

2014

Molecular and Cellular Biology

242

213

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“…We also examined the levels of eIF2α and AKT phosphorylation that are considered as the downstream signal transducers of the matrix and IMS unfolded protein stresses, 42,43 respectively. We found that both eIF2α and AKTwere hyperphosphorylated in dYME1L del flies (Figure 6b), further confirming the elevated UPR mt .…”

Section: Resultsmentioning

confidence: 99%

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Liu

Daniels

et al. 2015

Cell Death Differ

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Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L del ). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L del flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L del flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.

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“…While UPR mt was first discovered in mammals (Martinus et al, 1996), the molecular mechanism involved has been more extensively studied in the model organism Caenorhabditis elegans (Pellegrino et al, 2013). Worm strains, expressing a GFP reporter fused to promoters of the mitochondrial chaperones HSP-6 and HSP-60 (homologs of mammalian mtHSP70 and HSP60, respectively), were used to evaluate the activation of the UPR mt pathway.…”

Section: Proteostasis In Mitochondria the Upr Mtmentioning

confidence: 99%

The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease

Jovaisaite

Mouchiroud

Auwerx

2014

Journal of Experimental Biology

296

217

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The ability to respond to various intracellular and/or extracellular stresses allows the organism to adapt to changing environmental conditions and drives evolution. It is now well accepted that a progressive decline of the efficiency of stress response pathways occurs with aging. In this context, a correct proteostasis is essential for the functionality of the cell, and its dysfunction has been associated with protein aggregation and age-related degenerative diseases. Complex response mechanisms have evolved to deal with unfolded protein stress in different subcellular compartments and their moderate activation translates into positive effects on health. In this review, we focus on the mitochondrial unfolded protein response (UPR mt ), a response to proteotoxic stress specifically in mitochondria, an organelle with a wide array of fundamental functions, most notably the harvesting of energy from food and the control of cell death. We compare UPR mt with the extensively characterized cytosolic heat shock response (HSR) and the unfolded protein response in endoplasmic reticulum (UPR ER ), and discuss the current knowledge about UPR mt signaling pathways as well as their potential involvement in physiology.

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Signaling the mitochondrial unfolded protein response

Cited by 310 publications

References 102 publications

SirT3 Regulates the Mitochondrial Unfolded Protein Response

SirT3 Regulates the Mitochondrial Unfolded Protein Response

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease

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