A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60

Kumar, Rahul; Chaudhary, Ajay Kumar; Woytash, Jordan; Inigo, Joseph R.; Gokhale, Abhiram; Bshara, Wiam; Attwood, Kristopher; Wang, Jianmin; Spernyak, Joseph A.; Rath, Eva; Yadav, Neelu; Haller, Dirk; Goodrich, David W.; Tang, Dean G.; Chandra, Dhyan

doi:10.1172/jci149906

Cited by 36 publications

(20 citation statements)

References 93 publications

(125 reference statements)

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“…Moreover, the mt UPR is critical in adapting to overnutrition-induced stress, improving hepatic fatty acid oxidation and mitochondrial complex activities [40]. Meanwhile, mitochondrial HSP60 is a key component of the mt UPR, improving metabolic stress and cell survival [41]. This study demonstrates the mito-protective role of HSP60 in facilitating liver and adipose tissue to accommodate HFD-induced metabolic stress.…”

Section: Discussionmentioning

confidence: 72%

Chaperonin counteracts diet-induced non-alcoholic fatty liver disease by aiding sirtuin 3 in the control of fatty acid oxidation

Weng

Shen

et al. 2023

Diabetologia

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Aims/hypothesis The mitochondrial chaperonin heat shock protein (HSP) 60 is indispensable in protein folding and the mitochondrial stress response; however, its role in nutrient metabolism remains uncertain. This study investigated the role of HSP60 in diet-induced non-alcoholic fatty liver disease (NAFLD). Methods We studied human biopsies from individuals with NAFLD, murine high-fat-diet (HFD; a diet with 60% energy from fat)-induced obesity (DIO), transgenic (Tg) mice overexpressing Hsp60 (Hsp60-Tg), and human HepG2 cells transfected with HSP60 cDNA or with HSP60 siRNA. Histomorphometry was used to assess hepatic steatosis, biochemistry kits were used to measure insulin resistance and glucose tolerance, and an automated home cage phenotyping system was used to assess energy expenditure. Body fat was assessed using MRI. Macrophage infiltration, the lipid oxidation marker 4-hydroxy-2-nonenal (4-HNE) and the oxidative damage marker 8-hydroxy-2′-deoxyguanosine (8-OHdG) were detected using immunohistochemistry. Intracellular lipid droplets were evaluated by Nile red staining. Expression of HSP60, and markers of lipogenesis and fatty acid oxidation were quantified using RT-PCR and immunoblotting. Investigations were analysed using the twoway ANOVA test. Results Decreased HSP60 expression correlated with severe steatosis in human NAFLD biopsies and murine DIO. Hsp60-Tg mice developed less body fat, had reduced serum triglyceride levels, lower levels of insulin resistance and higher serum adiponectin levels than wild-type mice upon HFD feeding. Respiratory quotient profile indicated that fat in Hsp60-Tg mice Shao-Wen Weng and Jian-Ching Wu contributed equally to this study.

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Section: Discussionmentioning

confidence: 72%

Chaperonin counteracts diet-induced non-alcoholic fatty liver disease by aiding sirtuin 3 in the control of fatty acid oxidation

Weng

Shen

et al. 2023

Diabetologia

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“…Current findings clearly suggest that cancer cells are highly reliant on the UPR mt for growth and progression, and therefore, aggressive and resistant cancers such as PCa possess robust activation of UPR mt [255,256], which could be targeted for developing novel therapies to cure cancer. Recently, we have identified an inhibitor of UPR mt , a promising new anticancer agent for cancer such as PCa.…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer

Inigo

Chandra

2022

J Hematol Oncol

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Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt.

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“…HSF1 is essential for mitochondrial chaperones and protease transcription, especially during mtUPR, thus acting as a mitochondrial function guardian upon impaired protein homeostasis ( Katiyar et al, 2020 ). For instance, mtUPR inhibitors disrupt the interaction and cooperation of mitochondrial chaperones and proteases, triggering metabolic stress and arresting cell proliferation, suggesting that mtUPR is essential for tumorigenesis ( Kumar et al, 2022 ).…”

Section: Role Of Mitochondria In Protein Aggregationmentioning

confidence: 99%

Mitochondria inter-organelle relationships in cancer protein aggregation

Genovese

Fornetti

Ruocco

2022

Front. Cell Dev. Biol.

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Mitochondria are physically associated with other organelles, such as ER and lysosomes, forming a complex network that is crucial for cell homeostasis regulation. Inter-organelle relationships are finely regulated by both tether systems, which maintain physical proximity, and by signaling cues that induce the exchange of molecular information to regulate metabolism, Ca2+ homeostasis, redox state, nutrient availability, and proteostasis. The coordinated action of the organelles is engaged in the cellular integrated stress response. In any case, pathological conditions alter functional communication and efficient rescue pathway activation, leading to cell distress exacerbation and eventually cell death. Among these detrimental signals, misfolded protein accumulation and aggregation cause major damage to the cells, since defects in protein clearance systems worsen cell toxicity. A cause for protein aggregation is often a defective mitochondrial redox balance, and the ER freshly translated misfolded proteins and/or a deficient lysosome-mediated clearance system. All these features aggravate mitochondrial damage and enhance proteotoxic stress. This review aims to gather the current knowledge about the complex liaison between mitochondria, ER, and lysosomes in facing proteotoxic stress and protein aggregation, highlighting both causes and consequences. Particularly, specific focus will be pointed to cancer, a pathology in which inter-organelle relations in protein aggregation have been poorly investigated.

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A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60

Cited by 36 publications

References 93 publications

Chaperonin counteracts diet-induced non-alcoholic fatty liver disease by aiding sirtuin 3 in the control of fatty acid oxidation

Chaperonin counteracts diet-induced non-alcoholic fatty liver disease by aiding sirtuin 3 in the control of fatty acid oxidation

The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer

Mitochondria inter-organelle relationships in cancer protein aggregation

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