The Interaction of Mitochondrial Biogenesis and Fission/Fusion Mediated by PGC-1α Regulates Rotenone-Induced Dopaminergic Neurotoxicity

Peng, Kaige; Yang, Likui; Wang, Jian; Ye, Feng; Dan, Guorong; Zhao, Yuanpeng; Cai, Ying; Cui, Zhihong; Ao, Lin; Liu, Jinyi; Zou, Zhongmin; Sai, Yan; Cao, Jia

doi:10.1007/s12035-016-9944-9

Cited by 124 publications

(77 citation statements)

References 43 publications

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“…We have previously reported acute loss of mitochondrial membrane potential (quantified using MitoTracker ® ; Smirnova et al 2016) which could lead to fission defects. Studies have shown that inhibition of mitochondrial fission or promotion of mitochondrial fusion has protective effects in rotenone-induced neurotoxicity (Peng et al 2017), and studies have documented rotenone-induced effects on mitochondrial trafficking and movement (Fang et al 2016; Haddad and Nakamura 2015; Borland et al 2008). Mitochondria undergo dynamic changes using fusion and fission to maintain function and morphology during stress (Knott et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondria undergo dynamic changes using fusion and fission to maintain function and morphology during stress (Knott et al 2008). Imbalances in these mechanisms and fragmented mitochondria have been found in PD patients and only recently in vitro (Reddy 2008; Peng et al 2017). The analysis of mitochondria number also allowed us to confirm that the differences observed in complex I activity and ATP were not due to changes in the number of mitochondria.…”

Section: Discussionmentioning

confidence: 99%

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Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone

et al. 2018

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To date, most in vitro toxicity testing has focused on acute effects of compounds at high concentrations. This testing strategy does not reflect real-life exposures, which might contribute to long-term disease outcome. We used a 3D-human dopaminergic in vitro LUHMES cell line model to determine whether effects of short-term rotenone exposure (100 nM, 24 h) are permanent or reversible. A decrease in complex I activity, ATP, mitochondrial diameter, and neurite outgrowth were observed acutely. After compound removal, complex I activity was still inhibited; however, ATP levels were increased, cells were electrically active and aggregates restored neurite outgrowth integrity and mitochondrial morphology. We identified significant transcriptomic changes after 24 h which were not present 7 days after wash-out. Our results suggest that testing short-term exposures in vitro may capture many acute effects which cells can overcome, missing adaptive processes, and long-term mechanisms. In addition, to study cellular resilience, cells were re-exposed to rotenone after wash-out and recovery period. Pre-exposed cells maintained higher metabolic activity than controls and presented a different expression pattern in genes previously shown to be altered by rotenone. NEF2L2, ATF4, and EAAC1 were downregulated upon single hit on day 14, but unchanged in pre-exposed aggregates. DAT and CASP3 were only altered after re-exposure to rotenone, while TYMS and MLF1IP were downregulated in both single-exposed and pre-exposed aggregates. In summary, our study shows that a human cell-based 3D model can be used to assess cellular adaptation, resilience, and long-term mechanisms relevant to neurodegenerative research.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2250-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone

et al. 2018

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“…Generally, mitochondrial fission leads to the production of small mitochondrial fragments, resulting in lower MMP. In several disease models, such as Parkinson’s or Huntington’s diseases, relatively more mitochondrial fissions are observed in diseased neuronal cells (Manczak and Reddy, 2015; Peng et al, 2016). Furthermore, our truncated ATXN3 model also revealed more mitochondrial fissions ( Figure 3 ), suggesting that mitochondrial fission is a common characteristic of neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models

Hsu

Jhang

Cheng

et al. 2017

Front. Mol. Neurosci.

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Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo.

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“…The outer mitochondrial membrane family of fusion and fission proteins has recently garnered significant interest in multiple aspects of mitochondrial function (Chen et al, 2010; Cho et al, 2010; Elgass et al, 2013; Huang et al, 2007; Peng et al, 2017; Poole et al, 2008; Youle and van der Bliek, 2012; Yue et al, 2014). There has been a much greater focus on fission proteins and their role in disease than on fusion proteins (Corazao-Rozas et al, 2016; Elgass et al, 2013; Youle and van der Bliek, 2012).…”

Section: Discussionmentioning

confidence: 99%

Age-related accumulation of phosphorylated mitofusin 2 protein in retinal ganglion cells correlates with glaucoma progression

Nivison

Ericson

Green

et al. 2017

Experimental Neurology

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Dysregulation of axonal bioenergetics is likely a key mechanism in the initiation and progression of age-related neurodegenerative diseases. Glaucoma is a quintessential neurodegenerative disorder characterized by progressive deterioration of the optic nerve (ON) and eventual death of retinal ganglion cells (RGCs). Age and elevation of intraocular pressure are key risk factors in glaucoma, but the common early hallmarks of decreased axonal transport and increased bioenergetic vulnerability likely underlie disease initiation. We examined the correlation between bioenergetics and axonal transport with mitochondrial mutation frequency and post-translational modifications of mitofusin 2 (Mfn2) in RGCs during glaucoma progression. No increase in the frequency of mtDNA mutations was detected, but we observed significant shifts in mitochondrial protein species. Mfn2 is a fusion protein that functions in mitochondrial biogenesis, maintenance, and mitochondrial transport. We demonstrate that Mfn2 accumulates selectively in RGCs during glaucomatous degeneration, that two novel states of Mfn2 exist in retina and ON, and identify a phosphorylated form that selectively accumulates in RGCs, but is absent in ON. Phosphorylation of Mfn2 is correlated with higher ubiquitination, and failure of the protein to reach the ON. Together, these data suggest that post-translational modification of Mfn2 is associated with its dysregulation during a window of metabolic vulnerability that precedes glaucomatous degeneration. Future work to either manipulate expression of Mfn2 or to prevent its degradation could have therapeutic value in the treatment of neurodegenerative diseases where long-tract axons are vulnerable.

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The Interaction of Mitochondrial Biogenesis and Fission/Fusion Mediated by PGC-1α Regulates Rotenone-Induced Dopaminergic Neurotoxicity

Cited by 124 publications

References 43 publications

Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone

Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone

The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models

Age-related accumulation of phosphorylated mitofusin 2 protein in retinal ganglion cells correlates with glaucoma progression

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