Somatic Mitochondrial DNA Mutations Research Articles

Mitochondria: A source of potential biomarkers for non-communicable diseases.

Mitochondria, as an endosymbiont of eukaryotic cells, controls multiple cellular activities, including respiration, reactive oxygen speciesproduction, fatty acid synthesis, and death. Though the majority of functional mitochondrial proteins are translated through a nucleus-controlled process, very few of them (∼10%) are translated within mitochondria through their own machinery. Germline and somatic mutations in mitochondrial and nuclear DNA significantly impact mitochondrial homeostasis and function. Such modifications disturbing mitochondrial biogenesis, metabolism, or mitophagy eventually resulted in cellular pathophysiology. In this chapter, we discussed the impact of mitochondria and its dysfunction on several non-communicable diseases like cancer, diabetes, neurodegenerative, and cardiovascular problems. Mitochondrial dysfunction and its outcome could be screened by currently available omics-based techniques, flow cytometry, and high-resolution imaging. Such characterization could be evaluated as potential biomarkers to assess the disease burden and prognosis.

Mutational profiling of mitochondrial DNA reveals an epithelial ovarian cancer-specific evolutionary pattern contributing to high oxidative metabolism.

Epithelial ovarian cancer (EOC) heavily relies on oxidative phosphorylation (OXPHOS) and exhibits distinct mitochondrial metabolic reprogramming. Up to now, the evolutionary pattern of somatic mitochondrial DNA (mtDNA) mutations in EOC tissues and their potential roles in metabolic remodelling have not been systematically elucidated. Based on a large somatic mtDNA mutation dataset from private and public EOC cohorts (239 and 118 patients, respectively), we most comprehensively characterised the EOC-specific evolutionary pattern of mtDNA mutations and investigated its biological implication. Mutational profiling revealed that the mitochondrial genome of EOC tissues was highly unstable compared with non-cancerous ovary tissues. Furthermore, our data indicated the delayed heteroplasmy accumulation of mtDNA control region (mtCTR) mutations and near-complete absence of mtCTR non-hypervariable segment (non-HVS) mutations in EOC tissues, which is consistent with stringent negative selection against mtCTR mutation. Additionally, we observed a bidirectional and region-specific evolutionary pattern of mtDNA coding region mutations, manifested as significant negative selection against mutations in complex V (ATP6/ATP8) and tRNA loop regions, and potential positive selection on mutations in complex III (MT-CYB). Meanwhile, EOC tissues showed higher mitochondrial biogenesis compared with non-cancerous ovary tissues. Further analysis revealed the significant association between mtDNA mutations and both mitochondrial biogenesis and overall survival of EOC patients. Our study presents a comprehensive delineation of EOC-specific evolutionary patterns of mtDNA mutations that aligned well with the specific mitochondrial metabolic remodelling, conferring novel insights into the functional roles of mtDNA mutations in EOC tumourigenesis and progression.

Cultured lymphocytes' mitochondrial genome integrity is not altered by cladribine.

Cladribine tablets are a treatment for multiple sclerosis with effects on lymphocytes, yet its mode of action has not been fully established. Here, we analyzed the effects of cladribine on mitochondrial DNA integrity in lymphocytes. We treated cultured human T-cell lines (CCRF-CEM and Jurkat) with varying concentrations of cladribine to mimic the slow cell depletion observed in treated patients. The CCRF-CEM was more susceptible to cladribine than Jurkat cells. In both cells, mitochondrial protein synthesis, mitochondrial DNA copy number, and mitochondrial cytochrome-c oxidase-I mRNA mutagenesis was not affected by cladribine, while caspase-3 cleavage was detected in Jurkat cells at 100 nM concentration. Cladribine treatment at concentrations up to 10 nM in CCRF-CEM and 100 nM in Jurkat cells did not induce significant increase in mitochondrial DNA mutations. Peripheral blood mononuclear cells from eight multiple sclerosis patients and four controls were cultured with or without an effective dose of cladribine (5 nM). However, we did not find any differences in mitochondrial DNA somatic mutations in lymphocyte subpopulations (CD4+, CD8+, and CD19+) between treated versus nontreated cells. The overall mutation rate was similar in patients and controls. When different lymphocyte subpopulations were compared, greater mitochondrial DNA mutation levels were detected in CD8+ (P = 0.014) and CD4+ (P = 0.038) as compared to CD19+ cells, these differences were independent of cladribine treatment. We conclude that T cells have more detectable mitochondrial DNA mutations than B cells, and cladribine has no detectable mutagenic effect on lymphocyte mitochondrial genome nor does it impair mitochondrial function in human T-cell lines.

Abstract PR003: OXPHOS impairing mitochondrial DNA mutations suppress melanoma growth and metastatic progression

Abstract Cancers acquire somatic mitochondrial DNA (mtDNA) mutations undetected in surrounding tissues. Cancer-specific mtDNA mutations primarily constitute variants of unknown significance whose oncogenic consequences are poorly understood. Analysis of large-scale sequencing datasets suggests that human cancers generally select against severe mtDNA mutations; however, the presence of selective pressure on the mtDNA genome has yet to be experimentally demonstrated. Here we optimized a FACS-based protocol to reconstitute the highly metastatic human melanoma cell line A375 with exogenous mtDNA, thereby generating nuclear-isogenic cytoplasmic hybrid (cybrid) lines. Homoplasmic cybrids were generated exclusively harboring either exogenous wildtype mtDNA, mtDNA with partial loss of OXHPHOS function (SNPs in mt.ND1 (of Complex I) or mt.ATP6 (of Complex V)), or mtDNA with complete loss of OXPHOS function (derived from a human melanoma harboring a truncating frameshift mutation in mt.CO1 (of Complex IV)). Compared to wildtype cybrids, subcutaneous xenografts of ND1 and ATP6 cybrids into NOD–SCID Il2rg−/− (NSG) mice had elevated primary tumor ROS levels and similar primary tumor growth rates. Xenografts of our most dysfunctional OXPHOS cybrid, CO1, formed tumors albeit with lowered growth rates. Uniquely, the ND1 and CO1 xenografts respectively exhibited diminished metastatic burden and no metastatic burden. Our results suggest that OXPHOS impairing mtDNA mutations are tolerable during primary tumor growth but reduce the severity and incidence of metastasis. Lastly, we generated heteroplasmic A375 cybrids, harboring both wild-type and mutant alleles, and developed a ddPCR method to characterize allelic frequency with single-cell precision. Extended in vitro passage of the heteroplasmic cybrids failed to significantly shift the heteroplasmic mtDNA allelic frequency. However, following subcutaneous xenografting of the heteroplasmic cybrids, primary tumors significantly shifted their variant allele frequency to favor the wildtype allele. In summary, these results indicate that a functional mtDNA haplotype is not absolutely required for tumorigenesis but contributes to metastatic efficiency. In addition, we experimentally demonstrated the existence of selective pressure in favor of functional mtDNA during tumorigenesis. Citation Format: Spencer Shelton, Sara House, Vijayashree Ramesh, Zhengkang Chen, Claire Llamas, Alpaslan Tasdogan, Ralph DeBerardinis, Sean Morrison, Prashant Mishra. OXPHOS impairing mitochondrial DNA mutations suppress melanoma growth and metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR003.

Whole Mitochondrial Genome Analysis in Non-Small Cell Lung Carcinoma Reveals Unique Tumor-Specific Somatic Mutations.

Mitochondria and mitochondrial DNA have been suggested to play a role in cancer initiation and progression. Knowledge of mitochondrial DNA could provide a breakthrough to advance cancer management. To identify the mitochondrial DNA landscape in non-small cell lung carcinoma. The adenocarcinoma set consisted of 365 pairs of adenocarcinomas and normal lung tissues, whereas the metastasis set included 12 primary non-small cell carcinomas, 15 metastatic tumors, and their normal counterparts. Tumor-specific somatic variants were identified, and if a variant showed heteroplasmy, the proportion of minor alleles was evaluated. Variants with greater than 10% change in allele frequency between tumor and normal pairs were identified as "heteroplasmic shifts." Tumor-specific variants appeared throughout the whole mitochondrial genome, without a common hot spot. Distinct variant profiles were seen in 289 (79.18%) of all individual adenocarcinomas. The presence of a unique profile and the number and loading of heteroplasmic shifts in tumors increased with higher stage or lymph node metastasis, and were related to shorter survival. In the metastasis set, the primary tumor variants were generally found in metastatic tumors. This study shows that somatic mitochondrial DNA mutations present with diverse locations and unique profiles in each individual tumor, implying their clinicopathologic utility.

Clonal expansion and epigenetic inheritance of long-lasting NK cell memory

Clonal expansion of cells with somatically diversified receptors and their long-term maintenance as memory cells is a hallmark of adaptive immunity. Here, we studied pathogen-specific adaptation within the innate immune system, tracking natural killer (NK) cell memory to human cytomegalovirus (HCMV) infection. Leveraging single-cell multiomic maps of ex vivo NK cells and somatic mitochondrial DNA mutations as endogenous barcodes, we reveal substantial clonal expansion of adaptive NK cells in HCMV+ individuals. NK cell clonotypes were characterized by a convergent inflammatory memory signature enriched for AP1 motifs superimposed on a private set of clone-specific accessible chromatin regions. NK cell clones were stably maintained in specific epigenetic states over time, revealing that clonal inheritance of chromatin accessibility shapes the epigenetic memory repertoire. Together, we identify clonal expansion and persistence within the human innate immune system, suggesting that these mechanisms have evolved independent of antigen-receptor diversification.

Mitochondrial DNA mutations in ageing and cancer.

Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70. The pathologies of both ageing and cancer have been characterized by respective groups of molecular hallmarks, and while some features are divergent between the two pathologies, several are shared. Perturbed mitochondrial function is one such common hallmark, and this observation therefore suggests that mitochondrial alterations may be of significance in age‐related cancer development. There is now considerable evidence documenting the accumulation of somatic mitochondrial DNA (mtDNA) mutations in ageing human postmitotic and replicative tissues. Similarly, mutations of the mitochondrial genome have been reported in human cancers for decades. The plethora of functions in which mitochondria partake, such as oxidative phosphorylation, redox balance, apoptosis and numerous biosynthetic pathways, manifests a variety of ways in which alterations in mtDNA may contribute to tumour growth. However, the specific mechanisms by which mtDNA mutations contribute to tumour progression remain elusive and often contradictory. This review aims to consolidate current knowledge and describe future direction within the field.

Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients.

Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and EC samples have been shown to increase mitochondrial biogenesis. In cancer, mitochondrial DNA (mtDNA) heteroplasmy studies suggest that heteroplasmic variants encode predicted pathogenic proteins. We investigated the mtDNA genotypes within peri-normal and tumor specimens obtained from three individuals diagnosed with EC. DNA extracts from peri-normal and tumor tissues were used for mtDNA-specific next-generation sequencing and analyses of mtDNA content and topoisomers. The three tumors harbor heteroplasmic somatic mutations, and at least one mutation in each carcinoma is predicted to deleteriously alter a mtDNA-encoded protein. Somatic heteroplasmy linked to two mtDNA tRNA genes was found in separate tumors, and two heteroplasmic non-coding variants were identified in a single EC tumor. While two tumors had altered mtDNA content, all three displayed increased mtDNA catenanes. Our findings support that EC cells require wild-type mtDNA, but heteroplasmic mutations may alter mitochondrial metabolism to help promote cancer cell growth and proliferation.

Identifying Somatic Mitochondrial DNA Mutations.

Mitochondria are cellular organelles that play an essential role in eukaryotes, producing the energy needed for a cell to survive. Beyond the ~3.2Gb of nuclear genomic DNA, each human cell has hundreds of mitochondria which carry one or a few copies of the 16.5kb circular mitochondria DNA (mtDNA). Despite its small size, the circular genome encodes 37 genes, including 13 proteins that generate respiratory chain complexes together with other proteins of nuclear origin. Similar to nuclear genome, mtDNA in cancer cells frequently harbor somatically acquired alterations. Whole-genome or whole-exome sequencing of the tumor and its matched normal tissues (frequently blood or adjacent non-tumor tissues) enables sensitive and efficient detection of somatic mtDNA mutations. Because each cancer cell commonly carries hundreds to thousands of mtDNA copies, detection of mtDNA mutations is dependent on the heteroplasmic level of each mutation. Here, we describe strategies to accurately identify somatic mtDNA mutations in cancer genome studies.

Somatic mitochondrial DNA mutations in different grades of glioma.

Aim: Mitochondrial DNA (mtDNA) alterations play an important role in the multistep processes of cancer development. Gliomas are among the most diagnosed brain cancer. The relationship between mtDNA alterations and different grades of gliomas are still elusive. This study aimed to elucidate the profile of somatic mtDNA mutations in different grades of gliomas and correlate it with clinical phenotype. Materials & methods: Forty histopathologically confirmed glioma tissue samples and their matched blood were collected and subjected for mtDNA sequencing. Results & conclusion: About 75% of the gliomas harbored at least one somatic mutation in the mtDNA gene, and 45% of these mutations were pathogenic. Mutations were scattered across the mtDNA genome, and the commonest nonsynonymous mutations were located at complex I and IV of the mitochondrial respiratory chain. These findings may have implication for future research to determine the mitochondrial energetics and its downstream metabolomics on gliomas.

A Review on the Role of Mitochondrial DNA Mutations in Cancer

Mitochondria implement various cellular functions, including energy production through the electron transport chain by oxidative phosphorylation mechanism. These respiratory chains consist of several complexes and protein subunits which are encoded by nuclear and mitochondrial genes. Due to mutation susceptibility and repair limitation, more aberrations have occurred in mitochondrial DNA in comparison to nuclear DNA. Given the fact that mitochondrial DNA lacks introns, mutations almost occur in the coding sequence, which comprises a direct impact on its functions. Emerging evidence indicates that mutations in the mitochondrial DNA led to the production of reactive oxygen species, disrupted apoptosis, and tumor development. Studies reported various somatic and germline variants in mitochondrial DNA related to tumorigenesis. The D-loop region which is the starting point for replication and transcription of mitochondrial DNA is the most prevalent site of somatic mutations in solid tumors. The D-loop mutations also cause copy number variations which are gaining interest in studies of solid tumors including breast cancer, colon cancer, hepatocellular carcinomas, and prostate cancer. Most studies have reported a mitochondrial DNA reduction which subsequently prevents apoptosis and promotes metastasis. The mitochondrial DNA region-specific haplogroups are also involved in the sequence variations due to processes such as genetic drift and adaptive selection. This review article discusses the biology and function of mitochondria and related genes. By explanation of mitochondrial dysfunction caused by different kinds of alterations, we attempt to elucidate the role of mitochondria in tumorigenesis. Prominently published articles in this field were reviewed and the role of germline and somatic mutations of mitochondrial DNA have been investigated in common cancers. *Corresponding Author: Shirin Shahbazi; Email: sh.shahbazi@modares.ac.ir; ORCID iD: 0000-0002-7634-5350 Please cite this article as: Dahi F, Mortezanejad S, Nakhaee S, Geranpayeh L, Shahbazi S. A Review on the Role of Mitochondrial DNA Mutations in Cancer. Arch Med Lab Sci. 2021;7:1-12 (e18). https://doi.org/10.22037/amls.v7.34736

Papillary thyroid carcinoma tall cell variant shares accumulation of mitochondria, mitochondrial DNA mutations, and loss of oxidative phosphorylation complex I integrity with oncocytic tumors.

Papillary thyroid carcinoma tall cell variant (PTC‐TCV), a form of PTC regarded as an aggressive subtype, shares several morphologic features with oncocytic tumors. Pathogenic homoplasmic/highly heteroplasmic somatic mitochondrial DNA (mtDNA) mutations, usually affecting oxidative phosphorylation (OXPHOS) complex I subunits, are hallmarks of oncocytic cells. To clarify the relationship between PTC‐TCV and oncocytic thyroid tumors, 17 PTC‐TCV and 16 PTC non‐TCV controls (cPTC) were subjected to: (1) transmission electron microscopy (TEM) to assess mitochondria accumulation, (2) next‐generation sequencing to analyze mtDNA and nuclear genes frequently mutated in thyroid carcinoma, and (3) immunohistochemistry (IHC) for prohibitin and complex I subunit NDUFS4 to evaluate OXPHOS integrity. TEM showed replacement of cytoplasm by mitochondria in PTC‐TCV but not in cPTC cells. All 17 PTC‐TCV had at least one mtDNA mutation, totaling 21 mutations; 3/16 cPTC (19%) had mtDNA mutations (p < 0.001). PTC‐TCV mtDNA mutations were homoplasmic/highly heteroplasmic, 16/21 (76%) mapping within mtDNA‐encoded complex I subunits. MtDNA mutations in cPTC were homoplasmic in 2 cases and at low heteroplasmy in the third case, 2/3 mapping to mtDNA‐encoded complex I subunits; 2/3 cPTC with mtDNA mutations had small tall cell subpopulations. PTC‐TCV showed strong prohibitin expression and cPTC low‐level expression, consistent with massive and limited mitochondrial content, respectively. All 17 PTC‐TCV showed NDUFS4 loss (partial or complete) and 3 of 16 cPTC (19%) had (partial) NDUFS4 loss, consistent with lack of complex I integrity in PTC‐TCV (p < 0.001). IHC loss of NDUFS4 was associated with mtDNA mutations (p < 0.001). Four BRAF V600E mutated PTCs had loss of NDUSF4 expression limited to neoplastic cell subpopulations with tall cell features, indicating that PTCs first acquire BRAF V600E and then mtDNA mutations. Similar to oncocytic thyroid tumors, PTC‐TCV is characterized by mtDNA mutations, massive accumulation of mitochondria, and loss of OXPHOS integrity. IHC loss of NDUFS‐4 can be used as a surrogate marker for OXPHOS disruption and to reliably diagnose PTC‐TCV.

Pathogenic Mitochondrial DNA Mutation Load Inversely Correlates with Malignant Features in Familial Oncocytic Parathyroid Tumors Associated with Hyperparathyroidism-Jaw Tumor Syndrome.

While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer. We here report the first family with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome showing the inherited predisposition of four individuals to develop parathyroid oncocytic tumors. MtDNA sequencing revealed a rare ribosomal RNA mutation in the germline of all HPT-JT affected individuals whose pathogenicity was functionally evaluated via cybridization technique, and which was counter-selected in the most aggressive infiltrating carcinoma, but positively selected in adenomas. In all tumors different somatic mutations accumulated on this genetic background, with an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former both as modifiers of cancer fate and as prognostic markers.

A linear five-ring pyrrole-imidazole polyamide-triphenylphosphonium conjugate targeting a mitochondrial DNA mutation efficiently induces apoptosis of HeLa cybrid cells carrying the mutation

Somatic mutations in mitochondrial DNA may provide a new avenue for cancer therapy due to their associations to a number of cancers and a tendency of homoplasmicity. In consideration of mitochondrial features and its relatively small genome size, a nucleotide-based targeting approach is a considerably more promising option. To explore the efficacy of short linear N-methylpyrrole-N-methylimidazole polyamide (PI polyamide), we synthesized a five-ring short PI polyamide that provided sequence-specific homing for the A3243G mitochondrial mutation upon conjugation with triphenylphosphonium cation (TPP). This PI polyamide-TPP was able to induce cytotoxicity in HeLamtA3243G cybrid cells, while preserving preferential binding for oligonucleotides containing the A3243G motif from melting temperature assays. The PI polyamide-TPP also localized in the mitochondria in HeLamtA3243G cells and induced mitochondrial reactive oxygen species production, mitophagy and apoptosis in a mutation-specific fashion compared to the wild-type HeLamtHeLa cybrids; normal human dermal fibroblasts were also relatively unaffected to suggest discriminating selectivity for the mutant mitochondria, offering a novel outlook for cancer therapy via mitochondrial homing of short linear PIP-TPPs.

The relevance of mitochondrial DNA variants fluctuation during reprogramming and neuronal differentiation of human iPSCs.

SummaryThe generation of inducible pluripotent stem cells (iPSCs) is a revolutionary technique allowing production of pluripotent patient-specific cell lines used for disease modeling, drug screening, and cell therapy. Integrity of nuclear DNA (nDNA) is mandatory to allow iPSCs utilization, while quality control of mitochondrial DNA (mtDNA) is rarely included in the iPSCs validation process. In this study, we performed mtDNA deep sequencing during the transition from parental fibroblasts to reprogrammed iPSC and to differentiated neuronal precursor cells (NPCs) obtained from controls and patients affected by mitochondrial disorders. At each step, mtDNA variants, including those potentially pathogenic, fluctuate between emerging and disappearing, and some having functional implications. We strongly recommend including mtDNA analysis as an unavoidable assay to obtain fully certified usable iPSCs and NPCs.

Pathogenic Heteroplasmic Somatic Mitochondrial DNA Mutation Confers Platinum-Resistance and Recurrence of High-Grade Serous Ovarian Cancer.

PurposePlatinum resistance is a primary barrier to improving the survival rate of ovarian cancer. The relationship between mtDNA somatic mutations and response to platinum-based chemotherapy in ovarian cancer has not been well clarified.Patients and MethodsHere, we employed the next-generation sequencing (NGS) platform to identify mtDNA mutations of the unrelated high-grade serous ovarian cancer (HGSOC) patients.ResultsWe identified 569 germline variants and 28 mtDNA somatic mutations, and found the platinum-sensitive relapsed HGSOC patients had more synonymous mutations while the platinum-resistant relapsed HGSOC patients had more missense mutations in the mtDNA somatic mutations. Meanwhile, we found that the HGSOC patients who harbored heteroplasmic pathogenic mtDNA somatic mutations had significantly higher prevalence of both platinum-resistance and relapse than those without (80.0% versus 16.7%, p=0.035). Additionally, we observed that the tumor tissues had significantly higher lactate-to-pyruvate (L/P) ratio than the paired nontumor tissues (p<0.001), and L/P ratio of tumors with any heteroplasmic pathogenic mtDNA mutations was significantly higher than that of the tumors free of pathogenic mtDNA mutations (p=0.025).ConclusionOur findings indicate that these heteroplasmic pathogenic mtDNA somatic mutations may cause decreased respiratory chain activity and lead to the metabolism remodeling that seem to be beneficial for progression of both platinum-based chemotherapy resistance and relapse.

Metabolic benefits of mitochondrial DNA mutations

Smith, Whitehall et al. report evidence that somatic mutations in mitochondrial DNA that increase with age in the colorectal epithelium and that reduce oxidative phosphorylation can promote colorectal tumorigenesis.

Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis.

Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.

Mitochondrial DNA mutation exacerbates female reproductive aging via impairment of the NADH/NAD+ redox.

Mammals' aging is correlated with the accumulation of somatic heteroplasmic mitochondrial DNA (mtDNA) mutations. Whether and how aging accumulated mtDNA mutations modulate fertility remains unknown. Here, we analyzed oocyte quality of young (≤30 years old) and elder (≥38 years old) female patients and show the elder group had lower blastocyst formation rate and more mtDNA point mutations in oocytes. To test the causal role of mtDNA point mutations on infertility, we used polymerase gamma (POLG) mutator mice. We show that mtDNA mutation levels inversely correlate with fertility, interestingly mainly affecting not male but female fertility. mtDNA mutations decrease female mice's fertility by reducing ovarian primordial and mature follicles. Mechanistically, accumulation of mtDNA mutations decreases fertility by impairing oocyte's NADH/NAD+ redox state, which could be rescued by nicotinamide mononucleotide treatment. For the first time, we answer the fundamental question of the causal effect of age‐accumulated mtDNA mutations on fertility and its sex dependence, and show its distinct metabolic controlling mechanism.

Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss

The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. Somatic mitochondrial DNA (mtDNA) mutations accumulate with age in human tissues and mounting evidence suggests that they may be integral to the ageing process. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgAmut/mut mitochondrial DNA ‘mutator’ mouse. In vivo analyses showed an age-related loss of bone in both groups of mice; however, it was significantly accelerated in the PolgAmut/mut mice. This accelerated rate of bone loss is associated with significantly reduced bone formation rate, reduced osteoblast population densities, increased osteoclast population densities, and mitochondrial respiratory chain deficiency in osteoblasts and osteoclasts in PolgAmut/mut mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgAmut/mut cells. Finally, application of an exercise intervention to a subset of PolgAmut/mut mice showed no effect on bone mass or mineralised matrix formation in vitro. Our data demonstrate that mitochondrial dysfunction, a universal feature of human ageing, impairs osteogenesis and is associated with accelerated bone loss.