FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models

Deng, Jianwen; Wang, Peng; Chen, Xiaoping; Cheng, Haipeng; Liu, Jianghong; Fushimi, Kazuo; Zhu, Li; Wu, Jane Y.

doi:10.1073/pnas.1806655115

Cited by 96 publications

(106 citation statements)

References 48 publications

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“…Increasing evidence is supporting a role for mitochondrial dysfunction in the pathogenesis of ALS, however, it is unclear whether this is due to a direct role of ALS-related proteins in mitochondrial functionality, transport and/or dynamics or it is a consequence of neuronal degeneration, inflammation or the stress response. TDP-43 and FUS localise to mitochondria in neurons [94,95]. Whilst WT TDP-43 and FUS show limited localisation to these organelles, likely as a consequence of the very low levels present in the cytoplasm, ALS-linked mutants, show increased levels at the mitochondrion [94,95].…”

Section: Mitochondriamentioning

confidence: 99%

Cytoplasmic functions of TDP-43 and FUS and their role in ALS

Birsa

Bentham

Fratta

2020

Seminars in Cell & Developmental Biology

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TAR DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS) are RNA binding proteins (RBPs) primarily located in the nucleus, and involved in numerous aspects of RNA metabolism. Both proteins can be found to be depleted from the nucleus and accumulated in cytoplasmic inclusions in two major neurodegenerative conditions, amyotrophic lateral sclerosis and frontotemporal dementia. Recent evidences suggest that, in addition to their nuclear functions, both TDP-43 and FUS are involved in multiple processes in the cytoplasm, including mRNA stability and transport, translation, the stress response, mitochondrial and autophagy regulation. Here, we review the most recent advances in understanding their functions in the cytoplasm and how these are affected in disease.

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Section: Mitochondriamentioning

confidence: 99%

Cytoplasmic functions of TDP-43 and FUS and their role in ALS

Birsa

Bentham

Fratta

2020

Seminars in Cell & Developmental Biology

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“…FUS, when accumulated inside mitochondria, interacts with mitochondrial ATP synthase catalytic subunit ATP5B and reduces mitochondrial ATP synthesis. Accumulation of both wild-type FUS and the ALS-associated P525L mutant disrupts the formation of ATP synthase complex and suppresses the activity of ATP synthase, leading to loss of mitochondrial cristae, and thereby causing mitochondrial fragmentation ( Figure 2) [119]. Expression of both wild-type and ALS-associated mutant FUS disrupts ER-mitochondrial associations.…”

Section: Impaired Mitochondrial Dynamics and Plasticity In Mnd Pathogmentioning

confidence: 99%

Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective

Manohar

Wang

Hegde

2020

Cells

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Mitochondria plays privotal role in diverse pathways that regulate cellular function and survival, and have emerged as a prime focus in aging and age-associated motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Accumulating evidence suggests that many amyloidogenic proteins, including MND-associated RNA/DNA-binding proteins fused in sarcoma (FUS) and TAR DNA binding protein (TDP)-43, are strongly linked to mitochondrial dysfunction. Animal model and patient studies have highlighted changes in mitochondrial structure, plasticity, replication/copy number, mitochondrial DNA instability, and altered membrane potential in several subsets of MNDs, and these observations are consistent with the evidence of increased excitotoxicity, induction of reactive oxygen species, and activation of intrinsic apoptotic pathways. Studies in MND rodent models also indicate that mitochondrial abnormalities begin prior to the clinical and pathological onset of the disease, suggesting a causal role of mitochondrial dysfunction. Our recent studies, which demonstrated the involvement of specific defects in DNA break-ligation mediated by DNA ligase 3 (LIG3) in FUS-associated ALS, raised a key question of its potential implication in mitochondrial DNA transactions because LIG3 is essential for both mitochondrial DNA replication and repair. This question, as well as how wild-type and mutant MND-associated factors affect mitochondria, remain to be elucidated. These new investigation avenues into the mechanistic role of mitochondrial dysfunction in MNDs are critical to identify therapeutic targets to alleviate mitochondrial toxicity and its consequences. In this article, we critically review recent advances in our understanding of mitochondrial dysfunction in diverse subgroups of MNDs and discuss challenges and future directions.

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“…Furthermore, both R521G and R521H mutations of FUS have been associated with smaller mitochondria in motor neurons, deficits in axonal transport, and disruptions in the transference of vesicles between endoplasmic reticulum and mitochondria in iPSC-derived neurons from ALS patients (Tradewell et al, 2012). Moreover, an increase in mitochondrial FUS was shown to induce an increase in Fis1 and, as a result, an intensification of mitochondrial fragmentation and ROS production, in addition to mitochondrial depolarization, abnormal mitochondria transport along axons, and a decrease in ATP synthesis (Deng et al, 2020). Together, these studies suggest that unbalanced mitochondrial dynamics may be a common feature in ALS and this can, in turn, lead to a reduction in cell survival.…”

Section: Mitochondrial Dysfunction In Alsmentioning

confidence: 99%

Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenerative disorder. Although the pathogenesis of ALS is still not completely understood, numerous studies suggest that mitochondrial deregulation may be implicated in its onset and progression. Interestingly, mitochondrial deregulation has also been associated with changes in neural stem cells (NSC) proliferation, differentiation, and migration. In this review, we highlight the importance of mitochondrial function for neurogenesis, and how both processes are correlated and may contribute to the pathogenesis of ALS; we have focused primarily on preclinical data from animal models of ALS, since to date no studies have evaluated this link using human samples. As there is currently no cure and no effective therapy to counteract ALS, we have also discussed how improving neurogenic function by epigenetic modulation could benefit ALS. In support of this hypothesis, changes in histone deacetylation can alter mitochondrial function, which in turn might ameliorate cellular proliferation as well as neuronal differentiation and migration. We propose that modulation of epigenetics, mitochondrial function, and neurogenesis might provide new hope for ALS patients, and studies exploring these new territories are warranted in the near future.

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FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models

Cited by 96 publications

References 48 publications

Cytoplasmic functions of TDP-43 and FUS and their role in ALS

Cytoplasmic functions of TDP-43 and FUS and their role in ALS

Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective

Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment

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