Development and Dynamic Regulation of Mitochondrial Network in Human Midbrain Dopaminergic Neurons Differentiated from iPSCs

Summary Mitochondria are critical to neurogenesis, but the mechanisms of mitochondria in neurogenesis have not been well explored. We fully characterized mitochondrial alterations and function in relation to the development of human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons. Following directed differentiation of hiPSCs to DA neurons, mitochondria in these neurons exhibit pronounced changes during differentiation, including mature neurophysiology characterization and functional synaptic network formation. Inhibition of mitochondrial respiratory chains via application of complex IV inhibitor KCN (potassium cyanide) or complex I inhibitor rotenone restricted neurogenesis of DA neurons. These results demonstrated the direct importance of mitochondrial development and bioenergetics in DA neuronal differentiation. Our study also provides a neurophysiologic model of mitochondrial involvement in neurogenesis, which will enhance our understanding of the role of mitochondrial dysfunctions in neurodegenerative diseases.

• Publication year

  2016

• Venue

  Stem Cell Reports

• Publication date

  2016-09-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.stemcr.2016.08.014PMID 27666790PMCID 5063542
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Differentiation of Human Neural Stem Cells into Motor Neurons Stimulates Mitochondrial Biogenesis and Decreases Glycolytic Flux

  2015cited by this paper
• Physiological Characterisation of Human iPS-Derived Dopaminergic Neurons

  2014cited by this paper
• Drp1 Is Dispensable for Mitochondria Biogenesis in Induction to Pluripotency but Required for Differentiation of Embryonic Stem Cells

  2014influential reference
• Reprogramming to a pluripotent state modifies mesenchymal stem cell resistance to oxidative stress

  2014cited by this paper
• Pluripotent stem cell energy metabolism: an update

  2014cited by this paper
• Mitochondrial regulation in pluripotent stem cells.

  2013cited by this paper
• Proliferation of Murine Midbrain Neural Stem Cells Depends upon an Endogenous Sonic Hedgehog (Shh) Source

  2013cited by this paper
• Mitochondrial Function in Pluripotent Stem Cells and Cellular Reprogramming

  2013cited by this paper
• Progress and prospects in stem cell therapy

  2013cited by this paper
• Mitochondrial trafficking in neurons and the role of the Miro family of GTPase proteins.

  2013cited by this paper
• Oxidative stress inhibits adhesion and transendothelial migration, and induces apoptosis and senescence of induced pluripotent stem cells

  2013cited by this paper
• Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: New insight into the role of mitophagy in cell stemness

  2012cited by this paper
• Passaging and colony expansion of human pluripotent stem cells by enzyme-free dissociation in chemically defined culture conditions

  2012cited by this paper
• Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson’s Disease

  2012influential reference
• Physiological roles of mitochondrial reactive oxygen species.

  2012influential reference
• Mitochondrial biology and Parkinson's disease.

  2012cited by this paper
• MIRO1 influences the morphology and intracellular distribution of mitochondria during embryonic cell division in Arabidopsis

  2011cited by this paper
• Energy Metabolism in Human Pluripotent Stem Cells and Their Differentiated Counterparts

  2011cited by this paper
• Functional integration of dopaminergic neurons directly converted from mouse fibroblasts.

  2011influential reference
• Human Induced Pluripotent Stem Cells Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining Human Embryonic Stem Cell–like Metabolic Reprogramming

  2011cited by this paper
• Human Induced Pluripotent Stem Cell Lines Show Stress Defense Mechanisms and Mitochondrial Regulation Similar to Those of Human Embryonic Stem Cells

  2010cited by this paper
• Lmx1a and Lmx1b cooperate with Foxa2 to coordinate the specification of dopaminergic neurons and control of floor plate cell differentiation in the developing mesencephalon.

  2010influential reference
• Synapse formation in developing neural circuits.

  2009cited by this paper
• Enhancement of human embryonic stem cell pluripotency through inhibition of the mitochondrial respiratory chain.

  2009cited by this paper
• Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in Parkinsonian rats

  2008cited by this paper
• Mitochondria in neuroplasticity and neurological disorders.

  2008cited by this paper
• Transcriptional control of midbrain dopaminergic neuron development

  2006influential reference
• Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells.

  2006cited by this paper
• Identification of intrinsic determinants of midbrain dopamine neurons.

  2006influential reference
• Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and

  2006influential reference
• Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

  2006cited by this paper
• The Expression of Mitochondrial DNA Transcription Factors during Early Cardiomyocyte In Vitro Differentiation from Human Embryonic Stem Cells

  2005cited by this paper
• The Mitochondrial Production of Reactive Oxygen Species in Relation to Aging and Pathology

  2004influential reference
• The Mitochondrial Protein hFis1 Regulates Mitochondrial Fission in Mammalian Cells through an Interaction with the Dynamin-Like Protein DLP1

  2003cited by this paper
• Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development

  2003influential reference
• Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model

  2002influential reference
• Fate of Midbrain Dopaminergic Neurons Controlled by the Engrailed Genes

  2001influential reference
• Mitochondrial reactive oxygen species trigger hypoxia-induced transcription.

  1998cited by this paper
• The caudal limit of Otx2 gene expression as a marker of the midbrain/hindbrain boundary: a study using in situ hybridisation and chick/quail homotopic grafts.

  1996influential reference

• Organelle communication networks rewire to support lipid metabolism during neuronal differentiation

  2026cites this paper
• Nicotinamide counteracts Rotenone-induced mitochondrial and neuronal dysfunction in a translational early-life model

  2026cites this paper
• BRAFV600E induces key features of LCH in iPSCs with cell type–specific phenotypes and drug responses

  2024cites this paper
• Autism patient-derived SHANK2BY29X mutation affects the development of ALDH1A1 negative dopamine neuron

  2024cites this paper
• Neurogenesis and pesticides: news of no new neurons

  2023cites this paper
• Mitochondrial oxidative stress contributes to the pathological aggregation and accumulation of tau oligomers in Alzheimer's disease.

  2022cites this paper
• Effects of Changyu Daotan Decoction on Depression via Restoration of Mice Hippocampus and Alteration of Expression of Relevant Neurotrophic Factors

  2022cites this paper
• Silver Nanoparticles Suppress Retinoic Acid-Induced Neuronal Differentiation in Human-Derived Neuroblastoma SH-SY5Y Cells

  2022cites this paper
• Willin/FRMD6 Mediates Mitochondrial Dysfunction Relevant to Neuronal Aβ Toxicity

  2022influential citation
• Neural stem cells derived from human midbrain organoids as a stable source for treating Parkinson's disease: NSCs as a stable source for PD treatment.

  2021cites this paper
• Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties

  2021cites this paper
• Agrochemicals and neurogenesis.

  2020cites this paper
• Mitochondrial perturbation drives tau oligomers pathology in Alzheimer’s disease

  2020cites this paper
• Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

  2020cites this paper
• Uridine Prevents Negative Effects of OXPHOS Xenobiotics on Dopaminergic Neuronal Differentiation

  2019cites this paper
• Unraveling and overcoming hurdles in direct neuronal reprogramming

  2019cites this paper
• Modeling Genetic and Environment Interactions Relevant to Huntington's and Parkinson's Disease in Human Induced Pluripotent Stem Cells (hiPSCs)‐Derived Neurons

  2018cites this paper
• Accelerated dentinogenesis by inhibiting the mitochondrial fission factor, dynamin related protein 1.

  2018cites this paper
• Mitochondrial contributions to neuronal development and function

  2018cites this paper
• Mitochondrial retrograde signaling in the nervous system

  2018cites this paper
• Astrocytes Attenuate Mitochondrial Dysfunctions in Human Dopaminergic Neurons Derived from iPSC

  2018cites this paper
• Prenatal exposure to oxidative phosphorylation xenobiotics and late-onset Parkinson disease.

  2018cites this paper
• Rotenone exerts developmental neurotoxicity in a human brain spheroid model

  2018cites this paper
• Dietary Micronutrients Promote Neuronal Differentiation by Modulating the Mitochondrial‐Nuclear Dialogue

  2018cites this paper
• PPARs and Energy Metabolism Adaptation during Neurogenesis and Neuronal Maturation

  2018cites this paper
• Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone

  2018cites this paper
• Overexpression of endophilin A1 exacerbates synaptic alterations in a mouse model of Alzheimer’s disease

  2018cites this paper
• A possible key role of vision in the development of schizophrenia

  2018cites this paper
• T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease

  2018cites this paper
• Inhibition of Proliferation and Neurogenesis of Mouse Subventricular Zone Neural Stem Cells by a Mitochondrial Inhibitor Rotenone

  2018cites this paper
• PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer’s disease

  2017cites this paper
• Obtention de cellules souches humaines induites à la pluripotence à partir de cellules d'urine et leur différenciation neuronale

  2017cites this paper
• Less is more: Caloric regulation of neurogenesis and adult brain function

  2017cites this paper
• Mitochondrial trafficking in a mouse model of psychiatric illness

  2017cites this paper
• Insulin action in the brain: Roles in energy and glucose homeostasis

  2017cites this paper
• PINK 1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer ’ s disease

  2017cites this paper
• Direct Neuronal Reprogramming: Achievements, Hurdles, and New Roads to Success.

  2017cites this paper
• From the Cover: Manganese and Rotenone-Induced Oxidative Stress Signatures Differ in iPSC-Derived Human Dopamine Neurons

  2017cites this paper
• Mitochondrial metabolism in early neural fate and its relevance for neuronal disease modeling.

  2017influential citation