Impaired respiratory function in MELAS‐induced pluripotent stem cells with high heteroplasmy levels

Kodaira, Masaki; Hatakeyama, Hideyuki; Yuasa, Shinsuke; Seki, Tomohisa; Egashira, Toru; Tohyama, Shugo; Kuroda, Yusuke; Tanaka, Atsushi; Okata, Shinichiro; Hashimoto, Hisayuki; Kusumoto, Dai; Kunitomi, Akira; Takei, Makoto; Kashimura, Shin; Suzuki, Tomoyuki; Yozu, Gakuto; Shimojima, Masaya; Motoda, Chikaaki; Hayashiji, Nozomi; Saito, Yuki; Goto, Yu Ichi; Fukuda, Keiichi

doi:10.1016/j.fob.2015.03.008

Cited by 60 publications

(47 citation statements)

References 22 publications

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“…The biological cause of the drop in m.3243A>G levels in blood remains unknown, but it is consistent with continuous selection against haematopoietic stem cells with high mutation levels, a theory supported by simulations although not by induced pluripotent stem cell studies, which show marked bimodal segregation towards homoplasmy (Rajasimha et al , ; Hamalainen et al , ; Kodaira et al , ). Along with the inter ‐individual variation in the rate of decline, this suggests that any putative selection process is not universal.…”

Section: Discussionmentioning

confidence: 77%

mt DNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease

et al. 2018

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Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine N = 235, skeletal muscle N = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine (R 2 = 0.61–0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G‐harbouring individuals; increasing age and heteroplasmy contribute (R 2 = 0.27, P < 0.001). In muscle, heteroplasmy, age and mtDNA copy number explain a higher proportion of variability in disease burden (R 2 = 0.40, P < 0.001), although activity level and disease severity are likely to affect copy number. Whilst our data indicate that age‐corrected blood m.3243A>G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence disease severity.

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Section: Discussionmentioning

confidence: 77%

mt DNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease

et al. 2018

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“…Fibroblast reprogramming into induced pluripotent stem cells (iPSCs) may alter the heteroplasmy levels of any given mtDNA mutation [ 107 , 108 ]; however, it provides the opportunity to model specifi c mitochondrial defects [ 108 ] and screen potential therapeutic compounds [ 109 ]. A high mutation load of the m.3243A>G point mutation in iPSCs [ 108 ], differentiated neurons, and teratomas [ 107 ] was demonstrated to selectively impair complex I activity, in accordance with observations in MELAS patients. Interestingly, complex I-positive mitochondria were clustered around neuronal cell bodies and were eliminated by mitophagy with time [ 107 ].…”

Section: Cell Culture Modelsmentioning

confidence: 58%

Mitochondria, the Synapse, and Neurodegeneration

Chrysostomou¹,

Turnbull

2016

Mitochondrial Dysfunction in Neurodegenerative Disorders

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Mitochondria have a remarkably sophisticated structure and essential function within neurons that ensure normal synaptic transmission and maintained synaptic plasticity and hence normal information processing that can occur within the brain. The importance of mitochondria for synaptic structural preservation and activity is exemplifi ed by a high mitochondrial density at synaptic sites, whereas synaptic mitochondrial dysfunction or loss of mitochondria from synapses leads to synaptic abnormalities. The increasing body of evidence for mitochondrial defects, early synaptic dysfunction, and/or decreased synaptic density in common neurodegenerative disorders places these organelles at centre stage and establishes synaptic mitochondria as good candidates for drug targeting. In this chapter, we describe synaptic mitochondrial functions and present the evidence for synaptic disturbances in common neurodegenerative and mitochondrial diseases. Finally, we discuss the proposed mechanisms of neuronal loss with a focus on early synaptic loss. Keywords Neurons and MitochondriaThe highly specialized neuronal morphology allows neurons to form networks that control and facilitate all the information processing that occurs within the brain. Information is conveyed from one neuron to another via synaptic transmission, a process that is highly dependent on mitochondrial function. Hence, mitochondrial

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“…MELAS (Mitochondrial myopathy, Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) [93] was recently investigated using iPSCs. This was accomplished by several groups [93][94][95][96][97][98]. A common feature identified by these studies was that the original heteroplasmy level present in the patient fibroblasts can undergo changes before or during reprogramming.…”

Section: Ipsc Models Of Mitochondrial Neurological Diseasesmentioning

confidence: 99%

Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

Mlody

Lorenz

Inak

et al. 2016

Seminars in Cell & Developmental Biology

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The metabolic switch associated with the reprogramming of somatic cells to pluripotency has received increasing attention in recent years. However, the impact of mitochondrial and metabolic modulation on stem cell differentiation into neuronal/glial cells and related brain disease modeling still remains to be fully addressed. Here, we seek to focus on this aspect by first addressing brain energy metabolism and its inter-cellular metabolic compartmentalization. We then review the findings related to the mitochondrial and metabolic reconfiguration occurring upon neuronal/glial specification from pluripotent stem cells (PSCs). Finally, we provide an update of the PSC-based models of mitochondria-related brain disorders and discuss the challenges and opportunities that may exist on the road to develop a new era of brain disease modeling and therapy.3 Mitochondrial remodeling in cell fate specificationThe majority of cellular energy in form of ATP is provided through oxidative phosphorylation (OXPHOS) by mitochondria. Mitochondria are also involved in the metabolism of amino acids, fatty acids, and steroids, and contribute to cell signaling through the modulation of reactive oxygen species (ROS), calcium homeostasis, and apoptosis [1].Furthermore, intermediate metabolites can cross-talk to the nucleus acting as epigenetic regulators [2].In low oxygen environments, a typical conversion process of 1 molecule of glucose results into 2 molecules of ATP through glycolysis in the cytosol, which terminates with the secretion of lactate into the extracellular environment. Under normoxic conditions, the 2 molecules of pyruvate, generated through glycolysis, can enter the mitochondria and undergo further oxidation in the tricarboxylic acid (TCA) cycle, leading to the production of additional 34 molecules of ATP [3]. However, under conditions requiring high proliferative rates, this mitochondrial-based energy generation may be shut-down despite the presence of normal oxygen concentration [4]. This situation, known as aerobic glycolysis or Warburg effect, was first described by Otto Warburg in the context of cancer [5]. Recent studies demonstrated that a Warburg-like effect may also represent a defining feature of stem cells [6][7][8].Since distinct cell types have different energy demands, regulation of mitochondria may represent an essential process allowing the cells to meet their biological requirements.The metabolic identity of cells may in fact be influenced not only by changes in the expression of metabolic genes, but also by modulation of mitochondrial dynamics and mitochondrial DNA (mtDNA) copy number [9,10]. In particular, energy metabolism is shifted towards glycolysis in stem cells, whose mitochondria appear round-shaped with poorlydeveloped cristae [11,12]. This is in sharp contrast to cells with high energy demands, like muscle cells and neurons, where mitochondria are abundant in number and exhibit tubularlike morphology and cristae-rich structures [13]. 4As a consequence, acquisition of a distinct metabot...

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Impaired respiratory function in MELAS‐induced pluripotent stem cells with high heteroplasmy levels

Abstract: HighlightsWe modeled the mitochondrial disease MELAS by generating patient-specific iPS cells.MELAS-iPS cells show a wide variety of heteroplasmy levels.MELAS-iPS cells with high heteroplasmy levels showed impaired complex I activity.

Cited by 60 publications

References 22 publications

mt DNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease

mt DNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease

Mitochondria, the Synapse, and Neurodegeneration

Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

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