Mitochondrial respiratory complexes: Significance in human mitochondrial disorders and cancers

Vikramdeo, Kunwar Somesh; Sudan, Sarabjeet Kour; Singh, Ajay P.; Singh, Seema; Dasgupta, Santanu

doi:10.1002/jcp.30869

Cited by 14 publications

(11 citation statements)

References 297 publications

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“…The bioinformatics analysis revealed that the regulatory effect of METTL3 on the biological behavior of LPS-treated osteoclasts may be attributed to a mitochondrial dysfunction. Mitochondria are double-membrane organelles known as “energy generators” of the cells, converting nutrients and oxygen into ATP through oxidative phosphorylation [ 41 ]. As the master intracellular power producer, the proper function of mitochondria is critical for biological processes demanding energy, including cell survival, differentiation and activation [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

METTL3 Regulates Osteoclast Biological Behaviors via iNOS/NO-Mediated Mitochondrial Dysfunction in Inflammatory Conditions

Jin-lin

Fang

et al. 2023

IJMS

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Excessive differentiation of osteoclasts contributes to the disruption of bone homeostasis in inflammatory bone diseases. Methyltransferase-like 3 (METTL3), the core methyltransferase that installs an N6-methyladenosine (m6A) modification on RNA, has been reported to participate in bone pathophysiology. However, whether METTL3-mediated m6A affects osteoclast differentiation in inflammatory conditions remains unelucidated. In this study, we observed that the total m6A content and METTL3 expression decreased during LPS-induced osteoclastogenesis. After knocking down METTL3, we found reduced levels of the number of osteoclasts, osteoclast-related gene expression and bone resorption area. A METTL3 deficiency increased osteoclast apoptosis and pro-apoptotic protein expression. RNA sequencing analysis showed that differentially expressed genes in METTL3-deficient cells were mainly associated with the mitochondrial function. The expression of the mitochondrial function-related genes, ATP production and mitochondrial membrane potential decreased after METTL3 knockdown. Moreover, the most obviously upregulated gene in RNA-Seq was Nos2, which encoded the iNOS protein to induce nitric oxide (NO) synthesis. METTL3 knockdown increased the levels of Nos2 mRNA, iNOS protein and NO content. NOS inhibitor L-NAME rescued the inhibited mitochondrial function and osteoclast formation while suppressing osteoclast apoptosis in METTL3-silenced cells. Mechanistically, a METTL3 deficiency promoted the stability and expression of Nos2 mRNA, and similar results were observed after m6A-binding protein YTHDF1 knockdown. Further in vivo evidence revealed that METTL3 knockdown attenuated the inflammatory osteolysis of the murine calvaria and suppressed osteoclast formation. In conclusion, these data suggested that METTL3 knockdown exacerbated iNOS/NO-mediated mitochondrial dysfunction by promoting a Nos2 mRNA stability in a YTHDF1-dependent manner and further inhibited osteoclast differentiation and increased osteoclast apoptosis in inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

METTL3 Regulates Osteoclast Biological Behaviors via iNOS/NO-Mediated Mitochondrial Dysfunction in Inflammatory Conditions

Jin-lin

Fang

et al. 2023

IJMS

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“…The mitochondrial OXPHOS system plays a significant role in maintaining the energy balance of aggressively growing tumors 20 . The MG encoded machinery, constitutes the critical components of this OXPHOS pathway to generate 90% of the cellular ATP 7 . In concert with the nDNA‐encoded multiple RC proteins, the MG thus plays a pivotal role in driving the OXPHOS pathway and fueling tumor growth and progression.…”

Section: Discussionmentioning

confidence: 99%

“…In the OXPHOS system, RCI serves as the entry gate for the electron transport system to begin 7 . Alterations in RCI may lead to higher ROS production through electron leaking and inhibition of intrinsic apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Cancer cells constantly require a higher amount of energy for recurrent growth and progression. Mitochondria are the key cytoplasmic organelle in the cells to generate energy in the form of ATP 7,8 . Cancer cells have the remarkable ability to rewire mitochondrial energy generation cascade to their favor and achieve metastatic growth, thereby causing significant mortality.…”

Section: Introductionmentioning

confidence: 99%

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Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development

Vikramdeo,

Anand,

Sudan

et al. 2023

FASEB BioAdvances

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Early detection and recurrence prediction are challenging in triple‐negative breast cancer (TNBC) patients. We aimed to develop mitochondrial DNA (mtDNA)‐based liquid biomarkers to improve TNBC management. Mitochondrial genome (MG) enrichment and next‐generation sequencing mapped the entire MG in 73 samples (64 tissues and 9 extracellular vesicles [EV] samples) from 32 metastatic TNBCs. We measured mtDNA and cardiolipin (CL) contents, NDUFB8, and SDHB protein expression in tumors and in corresponding circulating EVs. We identified 168 nonsynonymous mtDNA mutations, with 73% (123/186) coding and 27% (45/168) noncoding in nature. Twenty percent of mutations were nucleotide transversions. Respiratory complex I (RCI) was the key target, which harbored 44% (74/168) of the overall mtDNA mutations. A panel of 11 hotspot mtDNA mutations was identified among 19%–38% TNBCs, which were detectable in the serum‐derived EVs with 82% specificity. Overall, 38% of the metastatic tumor‐signature mtDNA mutations were traceable in the EVs. An appreciable number of mtDNA mutations were homoplasmic (18%, 31/168), novel (14%, 23/168), and potentially pathogenic (9%, 15/168). The overall and RCI‐specific mtDNA mutational load was higher in women with African compared to European ancestry accompanied by an exclusive abundance of respiratory complex (RC) protein NDUFB8 (RCI) and SDHB (RCII) therein. Increased mtDNA (p < 0.0001) content was recorded in both tumors and EVs along with an abundance of CL (p = 0.0001) content in the EVs. Aggressive tumor‐signature mtDNA mutation detection and measurement of mtDNA and CL contents in the EVs bear the potential to formulate noninvasive early detection and recurrence prediction strategies.

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“…The upregulated OXPHOS pathway is closely related to the process of EMT and tumor metastasis [ 43 ]. In a relatively nutrient deficient environment, the oxidative stress reaction promotes tumor cells to produce lactic acid and other metabolites through glycolysis, and further supply the anabolism of tumor cells with OXPHOS as the main metabolic pathway, to promote tumor growth [ 44 ].…”

Section: Mitochondrial Metabolismmentioning

confidence: 99%

Metabolism in Cancer Stem Cells: Targets for Clinical Treatment

Wen

Xiaoyan

2022

Cells

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Cancer stem cells (CSCs) have high tumorigenicity, high metastasis and high resistance to treatment. They are the key factors for the growth, metastasis and drug resistance of malignant tumors, and are also the important reason for the occurrence and recurrence of tumors. Metabolic reprogramming refers to the metabolic changes that occur when tumor cells provide sufficient energy and nutrients for themselves. Metabolic reprogramming plays an important role in regulating the growth and activity of cancer cells and cancer stem cells. In addition, the immune cells or stromal cells in the tumor microenvironment (TME) will change due to the metabolic reprogramming of cancer cells. Summarizing the characteristics and molecular mechanisms of metabolic reprogramming of cancer stem cells will provide new ideas for the comprehensive treatment of malignant tumors. In this review, we summarized the changes of the main metabolic pathways in cancer cells and cancer stem cells.

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Mitochondrial respiratory complexes: Significance in human mitochondrial disorders and cancers

Cited by 14 publications

References 297 publications

METTL3 Regulates Osteoclast Biological Behaviors via iNOS/NO-Mediated Mitochondrial Dysfunction in Inflammatory Conditions

METTL3 Regulates Osteoclast Biological Behaviors via iNOS/NO-Mediated Mitochondrial Dysfunction in Inflammatory Conditions

Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development

Metabolism in Cancer Stem Cells: Targets for Clinical Treatment

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