Differential Protein Distribution between the Nucleus and Mitochondria: Implications in Aging

Lionaki, Eirini; Gkikas, Ilias; Tavernarakis, Nektarios

doi:10.3389/fgene.2016.00162

Cited by 36 publications

(32 citation statements)

References 147 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As the mitochondrial genome encodes only approximately 1% of the total mitochondrial proteome, and the remaining 99% of the mitochondrial proteins encoded by the nuclear genome, mitochondrial proteins synthesized in the cytosol require mitochondrial targeting signals (MTS) to facilitate their import into the mitochondria (Lionaki et al, 2016 ). Using MTS, gene therapies for mitochondrial disorders have been developed by delivering functional proteins and endonucleases to mitochondria with endogenous MTS (Farrar et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs

Wu²,

et al. 2018

View full text Add to dashboard Cite

Mitochondrial diseases are maternally inherited heterogeneous disorders that are primarily caused by mitochondrial DNA (mtDNA) mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruction of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells (MiPSCs) that harbored a high proportion of m.3243A>G mtDNA mutations and caused mitochondrial encephalomyopathy and stroke-like episodes (MELAS). We engineered mitochondrial-targeted transcription activator-like effector nucleases (mitoTALENs) and successfully eliminated the m.3243A>G mutation in MiPSCs. Off-target mutagenesis was not detected in the targeted MiPSC clones. Utilizing a dual fluorescence iPSC reporter cell line expressing a 3243G mutant mtDNA sequence in the nuclear genome, mitoTALENs displayed a significantly limited ability to target the nuclear genome compared with nuclear-localized TALENs. Moreover, genetically rescued MiPSCs displayed normal mitochondrial respiration and energy production. Moreover, neuronal progenitor cells differentiated from the rescued MiPSCs also demonstrated normal metabolic profiles. Furthermore, we successfully achieved reduction in the human m.3243A>G mtDNA mutation in porcine oocytes via injection of mitoTALEN mRNA. Our study shows the great potential for using mitoTALENs for specific targeting of mutant mtDNA both in iPSCs and mammalian oocytes, which not only provides a new avenue for studying mitochondrial biology and disease but also suggests a potential therapeutic approach for the treatment of mitochondrial disease, as well as the prevention of germline transmission of mutant mtDNA.Electronic supplementary materialThe online version of this article (10.1007/s13238-017-0499-y) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs

Wu²,

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Non-natural EMR signals have evolved tremendously in quantity and complexity over the last century. The need for perpetual cellular adaptation to randomly changing environmental fields consumes ATP and oxygen, and disturbs the anterograde and retrograde links between cell nucleus and mitochondria [56,57].…”

Section: Discussionmentioning

confidence: 99%

Magnetic Fields Trump Oxygen in Controlling the Death of Erythro-Leukemia Cells

Héroux

2019

Applied Sciences

View full text Add to dashboard Cite

Expansions in power and telecommunications systems have created a new electromagnetic environment. Here, we compare the death rate of human cancer cells in vitro in the pre-industrial electromagnetic environment of the past (“Zero Field”) with that of an electromagnetic environment typical of contemporary human exposures (“Incubator Field”). A cell incubator provides magnetic fields comparable to those in the current human environment. Steel shields divert those same fields away from cell preparations in the “pre-industrial” assays. Large changes in oxygen levels are provided by nitrogen or atmospheric gas over the cell cultures. Human cancer cells are then separated according to three categories: necrotic, early apoptotic, or late apoptotic. The results are compiled for two variables, magnetic field and oxygen, in 16 different situations (“Transitions”) likely to occur in the human body under present living conditions. We find that magnetic fields are a more powerful determinant of cell death than oxygen, and induce death by different mechanisms. This has important implications for the reproducibility of in vitro biological experiments focusing on cell survival or metabolism, and for public health. The rate and mechanisms of cell death are critical to many chronic human ailments such as cancer, neurological diseases, and diabetes.

show abstract

“…An alternative option to explain those effects is the function of COQ7 in the nucleus. Some studies have recently stated that, under certain conditions, mitochondrial proteins could be found in the nucleus to mediate a mitochondrial to nuclear retrograde signalling 31 . One of these proteins is COQ7, which has a nuclear targeting sequence, so could be located either in the nucleus or in the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Reduction in the levels of CoQ biosynthetic proteins is related to an increase in lifespan without evidence of hepatic mitohormesis

Rodríguez-Hidalgo

Luna-Sánchez

Hidalgo‐Gutiérrez

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Mitohormesis is an adaptive response induced by a mild mitochondrial stress that promotes longevity and metabolic health in different organisms. This mechanism has been proposed as the cause of the increase in the survival in Coq7+/− (Mclk1+/−) mice, which show hepatic reduction of COQ7, early mitochondrial dysfunction and increased oxidative stress. Our study shows that the lack of COQ9 in Coq9Q95X mice triggers the reduction of COQ7, COQ6 and COQ5, which results in an increase in life expectancy. However, our results reveal that the hepatic CoQ levels are not decreased and, therefore, neither mitochondrial dysfunction or increased oxidative stress are observed in liver of Coq9Q95X mice. These data point out the tissue specific differences in CoQ biosynthesis. Moreover, our results suggest that the effect of reduced levels of COQ7 on the increased survival in Coq9Q95X mice may be due to mitochondrial mechanisms in non-liver tissues or to other unknown mechanisms.

show abstract

Differential Protein Distribution between the Nucleus and Mitochondria: Implications in Aging

Cited by 36 publications

References 147 publications

Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs

Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs

Magnetic Fields Trump Oxygen in Controlling the Death of Erythro-Leukemia Cells

Reduction in the levels of CoQ biosynthetic proteins is related to an increase in lifespan without evidence of hepatic mitohormesis

Contact Info

Product

Resources

About