Mitochondrial dynamics in neurodegeneration

Itoh, Kie; Nakamura, Ken; Iijima, Miho; Sesaki, Hiromi

doi:10.1016/j.tcb.2012.10.006

Cited by 424 publications

(354 citation statements)

References 118 publications

Supporting

Mentioning

338

Contrasting

Unclassified

Order By: Relevance

“…6A). These morphologies have been linked to distinct cellular and mitochondrial metabolic states and conditions, supporting the model that mitochondrial function determines mitochondrial morphology and vice versa [20,148,[258][259][260]. Each of the three morphological states was associated with a distinct phenotype of mitochondrial parameters in primary human skin fibroblasts (Fig.…”

Section: Interpretation Of Quantitative Data For Mitochondrial Morphosupporting

confidence: 66%

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Tronstad¹,

Nooteboom²,

Nilsson³

et al. 2014

CPD

View full text Add to dashboard Cite

Running title: Regulation and quantification of mitochondrial morphology and content. Word count: 15,454 (total)Characters: 107,091 (including spaces); 92,067 (excluding spaces) Keywords: mitochondrial biogenesis, mitochondrial dynamics, mitochondrial degradation, living cells, TMRM, microscopy, segmentation, image analysis.Page 2 of 37 ABSTRACTMitochondria play a key role in signal transduction, redox homeostasis and cell survival, which extends far beyond their classical functioning in ATP production and energy metabolism. In living cells, mitochondrial content ("mitochondrial mass") depends on the cell-controlled balance between mitochondrial biogenesis and degradation. These processes are intricately linked to changes in net mitochondrial morphology and spatiotemporal positioning ("mitochondrial dynamics"), which are governed by mitochondrial fusion, fission and motility. It is becoming increasingly clear that mitochondrial mass and dynamics, as well as its ultrastructure and volume, are mechanistically linked to mitochondrial function and the cell. This means that proper quantification of mitochondrial morphology and content is of prime importance in understanding mitochondrial and cellular physiology in health and disease. This review first presents how cellular mitochondrial content is regulated at the level of mitochondrial biogenesis, degradation and dynamics. Next we discuss how mitochondrial dynamics and content can be analyzed with a special emphasis on quantitative live-cell microscopy strategies.

show abstract

Section: Interpretation Of Quantitative Data For Mitochondrial Morphosupporting

confidence: 66%

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Tronstad¹,

Nooteboom²,

Nilsson³

et al. 2014

CPD

View full text Add to dashboard Cite

show abstract

“…To reach that goal, it seems essential to provide energy levels close to those observed in healthy human brains, especially because several neurological disorders have been shown to be related to mitochondria dysfunctions (41)(42)(43). The mammalian brain uses glucose as one of its main sources of energy (44).…”

Section: Brainphys Basal Medium Better Mimics the Human Brain's Energymentioning

confidence: 99%

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

Bardy

Hurk

Eames

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

343

363

View full text Add to dashboard Cite

Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro.

show abstract

“…Mitochondria are dynamic organelles that require continuous fission and fusion to maintain integrity: fusion allows the exchange of contents, and fission effectively lowers the fraction of defective mitochondria [20]. Thus, an appropriate equilibrium between fission and fusion is critical for normal mitochondrial function [21].…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

et al. 2018

View full text Add to dashboard Cite

Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in GbaL444P/WT knockin mice, the L444P heterozygous Gba mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy. In SHSY-5Y neuroblastoma cells, the overexpression of L444P GBA impeded mitochondrial priming and autophagy induction when endogenous lysosomal GBA activity remained intact. By contrast, genetic depletion of GBA inhibited lysosomal clearance of autophagic cargo. The link between heterozygous GBA mutations and impaired mitophagy was corroborated in postmortem brain tissue from PD patients carrying heterozygous GBA mutations, where we found increased mitochondrial content, mitochondria oxidative stress and impaired autophagy. Our findings thus suggest a mechanistic basis for mitochondrial dysfunction associated with GBA heterozygous mutations.Abbreviations: AMBRA1: autophagy/beclin 1 regulator 1; BECN1: beclin 1, autophagy related; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chloroyphenylhydrazone; CYCS: cytochrome c, somatic; DNM1L/DRP1: dynamin 1-like; ER: endoplasmic reticulum; GBA: glucosylceramidase beta; GBA-PD: Parkinson disease with heterozygous GBA mutations; GD: Gaucher disease; GFP: green fluorescent protein; LC3B: microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated form of microtubule-associated protein 1 light chain 3 beta; MitoGreen: MitoTracker Green; MitoRed: MitoTracker Red; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH transcription factor; NBR1: NBR1, autophagy cargo receptor; Non-GBA-PD: Parkinson disease without GBA mutations; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; ROS: reactive oxygen species; SNCA: synuclein alpha; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1/Porin: voltage dependent anion channel 1; WT: wild type

show abstract

Mitochondrial dynamics in neurodegeneration

Cited by 424 publications

References 118 publications

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

Contact Info

Product

Resources

About