OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

Schöpf, Bernd; Weißensteiner, Hansi; Schäfer, Georg; Fazzini, Federica; Charoentong, Pornpimol; Naschberger, Andreas; Rupp, Bernhard; Fendt, Liane; Bukur, Valesca; Giese, Irina; Sorn, Patrick; Sant'Anna-Silva, Ana Carolina Bastos; Iglesias-Gonzalez, Javier; Şahin, Uğur; Kronenberg, Florian; Gnaiger, Erich; Klocker, Helmut

doi:10.1038/s41467-020-15237-5

Cited by 90 publications

(102 citation statements)

References 76 publications

(104 reference statements)

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“…Beyond the Warburg effect, a metabolic shift towards complex II-dependent succinate oxidation was recently described as an adaptive mechanism to compensate for OXPHOS dysfunction in high-grade prostate cancers, mutant for the ND1 subunit of complex I [ 54 ]. As a response to the inhibition of glutamate and malate oxidation and to the subsequent electron transport loss across complex I, ND1-mutant cancer cells were found to produce ATP by aerobic respiration through complex II-mediated succinate oxidation [ 54 ]. This metabolic reprogramming was associated with shorter patient survival, highlighting the critical role of complex II and succinate in malignancies associated with complex I dysfunction [ 54 ].…”

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

“…As a response to the inhibition of glutamate and malate oxidation and to the subsequent electron transport loss across complex I, ND1-mutant cancer cells were found to produce ATP by aerobic respiration through complex II-mediated succinate oxidation [ 54 ]. This metabolic reprogramming was associated with shorter patient survival, highlighting the critical role of complex II and succinate in malignancies associated with complex I dysfunction [ 54 ].…”

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

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Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Nakhle

Rodriguez

Vignais

2020

IJMS

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Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.

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Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Nakhle

Rodriguez

Vignais

2020

IJMS

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“…In contrast, the presence of heteroplasmy affecting functionally relevant sites might be an indication for disease and is found in many human tumors [ 10 ]. In fact, our group could demonstrate the involvement of mtDNA mutations in several types of cancer [ 11 , 12 , 13 , 14 ]. Several studies reported a potential role of mtDNA mutations in OSCC [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Profiling of Mitochondrial DNA Heteroplasmy in a Prospective Oral Squamous Cell Carcinoma Study

Fendt

Fazzini

Weißensteiner

et al. 2020

Cancers

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While a shift in energy metabolism is essential to cancers, the knowledge about the involvement of the mitochondrial genome in tumorigenesis and progression in oral squamous cell carcinoma (OSCC) is still very limited. In this study, we evaluated 37 OSCC tumors and the corresponding benign mucosa tissue pairs by deep sequencing of the complete mitochondrial DNA (mtDNA). After extensive quality control, we identified 287 variants, 137 in tumor and 150 in benign samples exceeding the 1% threshold. Variant heteroplasmy levels were significantly increased in cancer compared to benign tissues (p = 0.0002). Furthermore, pairwise high heteroplasmy frequency difference variants (∆HF% > 20) with potential functional impact were increased in the cancer tissues (p = 0.024). Fourteen mutations were identified in the protein-coding region, out of which thirteen were detected in cancer and only one in benign tissue. After eight years of follow-up, the risk of mortality was higher for patients who harbored at least one ∆HF% > 20 variant in mtDNA protein-coding regions relative to those with no mutations (HR = 4.6, (95%CI = 1.3–17); p = 0.019 in primary tumor carriers). Haplogroup affiliation showed an impact on survival time, which however needs confirmation in a larger study. In conclusion, we observed a significantly higher accumulation of somatic mutations in the cancer tissues associated with a worse prognosis.

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“…Interestingly, RNA-seq analysis of prostate tissues shows remarkable enrichment of OXPHOS-related genes in CRPC ( 66 ). Moreover, a study analyzing substrate-specific OXPHOS capacities using primary human prostate tissues revealed that the malignant tissues exhibits a significant metabolic shift toward higher succinate oxidation by complex II, particularly in high-grade prostate tumors ( 67 ).…”

Section: Oxphos With Lncrnamentioning

confidence: 99%

Long Non-coding RNAs Involved in Metabolic Alterations in Breast and Prostate Cancers

et al. 2020

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Breast and prostate cancers are the most prevalent cancers in females and males, respectively. These cancers exhibit sex hormone dependence and thus, hormonal therapies are used to treat these cancers. However, acquired resistance to hormone therapies is a major clinical problem. In addition, certain portions of these cancers initially exhibit hormone-independence due to the absence of sex hormone receptors. Therefore, precise and profound understanding of the cancer pathophysiology is required to develop novel clinical strategies against breast and prostate cancers. Metabolic reprogramming is currently recognized as one of the hallmarks of cancer, as exemplified by the alteration of glucose metabolism, oxidative phosphorylation, and lipid metabolism. Dysregulation of metabolic enzymes and their regulators such as kinases, transcription factors, and other signaling molecules contributes to metabolic alteration in cancer. Moreover, accumulating lines of evidence reveal that long non-coding RNAs (lncRNAs) regulate cancer development and progression by modulating metabolism. Understanding the mechanism and function of lncRNAs associated with cancer-specific metabolic alteration will therefore provide new knowledge for cancer diagnosis and treatment. This review provides an overview of recent studies regarding the role of lncRNAs in metabolism in breast and prostate cancers, with a focus on both sex hormone-dependent and -independent pathways.

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OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

Cited by 90 publications

References 76 publications

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Profiling of Mitochondrial DNA Heteroplasmy in a Prospective Oral Squamous Cell Carcinoma Study

Long Non-coding RNAs Involved in Metabolic Alterations in Breast and Prostate Cancers

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