Cell and animal models of mtDNA biology: progress and prospects

Khan, Shaharyar M.; Smigrodzki, Rafal; Swerdlow, Russell H.

doi:10.1152/ajpcell.00224.2006

Cited by 37 publications

(25 citation statements)

References 138 publications

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“…The main advantage of these cybrids is the ability to investigate whether phenotypes and biochemical changes are related to changes in the nDNA or mtDNA. Furthermore, cybrid models enable the investigation of in vitro and in vivo effects of different mtDNA mutations in cancer cell lines and tumors with the same nuclear background [215]. A possible disadvantage is the dependency on naturally occurring patient mtDNA variations.…”

Section: In Vitromentioning

confidence: 99%

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

Gisbergen

Voets

Starmans

et al. 2015

Mutation Research/Reviews in Mutation Research

170

151

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Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like ρ(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease.

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Section: In Vitromentioning

confidence: 99%

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

Gisbergen

Voets

Starmans

et al. 2015

Mutation Research/Reviews in Mutation Research

170

151

View full text Add to dashboard Cite

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“…Presently, this technique is used for studying many human disorders, such as cancer , mitochondriopathies (Swerdlow , 2007 ) and neurodegenerative diseases, such as AD (Cardoso et al , 2004 ), PD (Esteves et al , 2008 ) and HD (Swerdlow et al , 1999 ;Ferreira et al , 2010Ferreira et al , , 2011. This approach allows distinct applications, including the study of mitochondrial DNA mutations, assessing the integrity of the transferred mtDNA, compatibility biogenomic and/or mitochondrial abnormalities (Khan et al , 2007 ;Swerdlow , 2007 ) and, more recently, as a platform for the development of new therapies (Trimmer and Bennett , 2009 ).…”

Section: Cybrids: a Model To Study Mitochondrial Biology In Hdmentioning

confidence: 99%

Mitochondrial and metabolic-based protective strategies in Huntington’s disease: the case of creatine and coenzyme Q

Naia¹,

Ribeiro²,

Rego³

2011

Revneuro

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Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion of CAG repeats in the HD gene encoding for huntingtin (Htt), resulting in progressive death of striatal neurons, with clinical symptoms of chorea, dementia and dramatic weight loss. Metabolic and mitochondrial dysfunction caused by the expanded polyglutamine sequence have been described along with other mechanisms of neurodegeneration previously described in human tissues and animal models of HD. In this review, we focus on mitochondrial and metabolic disturbances affecting both the central nervous system and peripheral cells, including mitochondrial DNA damage, mitochondrial complexes defects, loss of calcium homeostasis and transcriptional deregulation. Glucose abnormalities have also been described in peripheral tissues of HD patients and in HD animal and cellular models. Moreover, there are no effective neuroprotective treatments available in HD. Thus, we briefly discuss the role of creatine and coenzyme Q10 that target mitochondrial dysfunction and impaired bioenergetics and have been previously used in HD clinical trials.

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“…The recent development of a protein-based mtDNA transfection (protofection), which utilizes an engineered human mitochondrial transcription factor A (TFAM) protein, provides opportunities to access the mitochondria for therapeutic interventions. 141–143 The components of the engineered protein are based on the naturally occurring, non-immunogenic human proteins TFAM and mitochondrial localization sequence/signal (MLS), to target mitochondria. Studies conducted with sporadic PD cybrid cells have demonstrated the potential for this technology to restore respiration, increase mtDNA levels and gene expression, and increase levels of proteins associated with the electron transport chain.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Stem Cell-Based Models and Therapies for Neurodegenerative Diseases

Iyer

Alsayegh

Abraham

et al. 2009

Crit Rev Biomed Eng

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Multiple neurodegenerative disorders typically result from irrevocable damage and improper functioning of specialized neuronal cells or populations of neuronal cells. These disorders have the potential to contribute to an already overburdened health care system unless the progression of neurodegeneration can be altered. Progress in understanding neurodegenerative cell biology has been hampered by a lack of predictive and, some would claim, relevant cellular models. Additionally, the research needed to develop new drugs and determine methods for repair or replacement of damaged neurons is severely hampered by the lack of an adequate in vitro human neuron cell-based model. In this context, pluripotent stem cells and neural progenitors and their properties—including unlimited proliferation, plasticity to generate other cell types, and a readily available source of cells—pose an excellent alternative to ex vivo primary cultures or established immortalized cell lines in contributing to our understanding of neurodegenerative cell biology and our ability to analyze the therapeutic or cytotoxic effects of chemicals, drugs, and xenobiotics. Many questions that define the underlying “genesis” of the neuronal death in these disorders also remain unanswered, with evidence suggesting a key role for mitochondrial dysfunction. The assessment of stem cells, neural progenitors, and engineered adult cells can provide useful insights into neuronal development and neurodegenerative processes. Finally, the potential for a combination of cell- and gene-based therapeutics for neurodegenerative disorders is also discussed.

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Cell and animal models of mtDNA biology: progress and prospects

Abstract: Khan SM, Smigrodzki RM, Swerdlow RH. Cell and animal models of mtDNA biology: progress and prospects.

Cited by 37 publications

References 138 publications

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

Mitochondrial and metabolic-based protective strategies in Huntington’s disease: the case of creatine and coenzyme Q

Stem Cell-Based Models and Therapies for Neurodegenerative Diseases

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