Failure to Guard: Mitochondrial Protein Quality Control in Cancer

Friedlander, Joseph E.; Shen, Ning; Zeng, Aozhuo; Korm, Sovannarith; Feng, Hui

doi:10.3390/ijms22158306

Cited by 10 publications

(16 citation statements)

References 314 publications

(356 reference statements)

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“…Exciting new roles for chaperones and co-chaperones related to inflammation, autoimmune disorders, and the previously described diseases include mitochondrial and nuclear shuttling of cargo and chaperone activity within these organelles (Figure 1). We encourage the reader to consider several reviews that cover chaperone-organelle specific activities and their role in disease in greater detail [48][49][50][51][52][53][54][55][56].…”

Section: Autoimmune Disordersmentioning

confidence: 99%

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Altınok

Sanchez‐Hodge

Stewart

et al. 2021

Cells

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Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

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Section: Autoimmune Disordersmentioning

confidence: 99%

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Altınok

Sanchez‐Hodge

Stewart

et al. 2021

Cells

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“…Several Mitochondria Quality Control (MQC) pathways serve to maintain the integrity of mitochondria. MQC pathways sense changes in mitochondrial oxidative phosphorylation, membrane potential, proteostasis and translation of mitochondrial DNA encoded proteins (5)(6)(7). MQC pathways signal to cytosolic pathways that control the ATF4-Integrated Stress Response (ISR), an adaptive gene expression program controlling amino acid biosynthesis and transport, redox homeostasis and enhanced protein folding (5,8,9).…”

Section: Introductionmentioning

confidence: 99%

“…MQC pathways sense changes in mitochondrial oxidative phosphorylation, membrane potential, proteostasis and translation of mitochondrial DNA encoded proteins (5)(6)(7). MQC pathways signal to cytosolic pathways that control the ATF4-Integrated Stress Response (ISR), an adaptive gene expression program controlling amino acid biosynthesis and transport, redox homeostasis and enhanced protein folding (5,8,9). The ATF4-ISR facilitates adaptation to the tumor microenvironment and is shown to be a pharmacologically targetable tumor dependency (2,10).…”

Section: Introductionmentioning

confidence: 99%

“…MQC pathways signal to cytosolic pathways that control the ATF4-Integrated Stress Response (ISR), an adaptive gene expression program controlling amino acid biosynthesis and transport, redox homeostasis and enhanced protein folding (3,6,7). The ATF4-ISR facilitates adaptation to the tumor microenvironment and can be pharmacologically targeted (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1

Kostura¹,

Stocum²,

Hembrough³

et al. 2022

Preprint

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DLBCL are aggressive, rapidly proliferating tumors that critically depend on the ATF4-mediated integrated stress response (ISR) to adapt to stress caused by uncontrolled growth, such as hypoxia, amino acid deprivation and accumulation of misfolded proteins. Here we show that ISR hyperactivation is a targetable liability in DLBCL. We describe a novel class of compounds represented by BTM-3528 and BTM-3566, that activate the ISR though the mitochondrial protease OMA1. Treatment of tumor cells with compound leads to OMA1-dependent cleavage of DELE1 and OPA1, mitochondrial fragmentation, activation of the eIF2α-kinase HRI, cell growth arrest and apoptosis. Activation of OMA1 by BTM-3528 and BTM-3566 is mechanistically distinct from inhibitors of mitochondrial electron transport, as the compounds induce OMA1 activity in the absence of acute changes in respiration. We further identify the mitochondrial protein FAM210B as a negative regulator of BTM-3528 and BTM-3566 activity. Overexpression of FAM210B prevents both OMA1 activation and apoptosis. Notably, FAM210B expression is nearly absent in healthy germinal-center B-lymphocytes and in derived B-cell malignancies, revealing a fundamental molecular vulnerability which is targeted by BTM compounds. Both compounds induce rapid apoptosis across diverse DLBCL lines derived from activated B-cell, germinal center B-cell, and MYC-rearranged lymphomas. Once-daily oral dosing of BTM-3566 resulted in complete regression of xenografted human DLBCL SU-DHL-10 cells and complete regression in 6 of 9 DLBCL patient-derived xenografts. BTM-3566 represents a first- of-its kind approach of selectively hyperactivating the mitochondrial ISR for treating DLBCL.

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“…Termed protein quality control (PQC) [ 2 , 3 , 4 , 5 , 6 , 7 ], these molecular pathways guard against the accumulation of misfolded proteins in cells, which if left unchecked, may result in the malfunction of normal cellular processes. PQC is especially relevant to human biology where its breakdown is well known to play roles in the development of various disease states including neurodegeneration and cancer [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. In eukaryotic cells, the ubiquitin system, a signal transduction cascade that targets proteins for degradation, is a major regulator of PQC [ 16 , 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

The San1 Ubiquitin Ligase Avidly Recognizes Misfolded Proteins through Multiple Substrate Binding Sites

et al. 2021

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Cellular homeostasis depends on robust protein quality control (PQC) pathways that discern misfolded proteins from functional ones in the cell. One major branch of PQC involves the controlled degradation of misfolded proteins by the ubiquitin-proteasome system. Here ubiquitin ligases must recognize and bind to misfolded proteins with sufficient energy to form a complex and with an adequate half-life to achieve poly-ubiquitin chain formation, the signal for protein degradation, prior to its dissociation from the ligase. It is not well understood how PQC ubiquitin ligases accomplish these tasks. Employing a fully reconstituted enzyme and substrate system to perform quantitative biochemical experiments, we demonstrate that the yeast PQC ubiquitin ligase San1 contains multiple substrate binding sites along its polypeptide chain that appear to display specificity for unique misfolded proteins. The results are consistent with a model where these substrate binding sites enable San1 to bind to misfolded substrates avidly, resulting in high affinity ubiquitin ligase-substrate complexes.

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Failure to Guard: Mitochondrial Protein Quality Control in Cancer

Cited by 10 publications

References 314 publications

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1

The San1 Ubiquitin Ligase Avidly Recognizes Misfolded Proteins through Multiple Substrate Binding Sites

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