Mitochondrial SIRT3 and neurodegenerative brain disorders

Anamika, Anamika; Khanna, Archita; Acharjee, Papia; Acharjee, Arup; Trigun, Surendra Kumar

doi:10.1016/j.jchemneu.2017.11.009

Cited by 72 publications

(39 citation statements)

References 130 publications

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“…Additionally, previous studies have shown that αsyn interacts with TOM20 [61], a protein required for mitochondrial protein import, and decreases its function. SIRT3 is reported to exist in the cytoplasm in an inactive form and is recruited to the mitochondria upon stress [62], although the data presented here do not support cytosolic SIRT3 expression. It is tempting to speculate that TOM20 plays a role in the translocation of SIRT3 to mitochondria and that αsyn-induced deficit in protein import results in reduced mitochondrial SIRT3 levels thereby initiating the cascade of mitochondrial dysfunction that results in decreased mitochondrial bioenergetics.…”

Section: Discussioncontrasting

confidence: 96%

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

Park

Burgess

Faroqi

et al. 2020

Mol Neurodegeneration

136

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Background: Misfolding and aggregation of the presynaptic protein alpha-synuclein (αsyn) is a hallmark of Parkinson's disease (PD) and related synucleinopathies. Although predominantly localized in the cytosol, a body of evidence has shown that αsyn localizes to mitochondria and contributes to the disruption of key mitochondrial processes. Mitochondrial dysfunction is central to the progression of PD and mutations in mitochondrial-associated proteins are found in familial cases of PD. The sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD + )-dependent enzymes that play a broad role in cellular metabolism and aging. Interestingly, mitochondrial sirtuin 3 (SIRT3) plays a major role in maintaining mitochondrial function and preventing oxidative stress, and is downregulated in aging and age-associated diseases such as neurodegenerative disorders. Herein, we hypothesize that αsyn is associated with decreased SIRT3 levels contributing to impaired mitochondrial dynamics and biogenesis in PD. Methods: The level of mitochondrial SIRT3 was assessed in cells expressing oligomeric αsyn within the cytosolic and mitochondrial-enriched fractions. Mitochondrial integrity, respiration, and health were examined using several markers of mitochondrial dynamics and stress response and by measuring the rate of oxygen consumption (OCR). Our findings were validated in a rodent model of PD as well as in human post-mortem Lewy body disease (LBD) brain tissue.Results: Here, we demonstrate that αsyn associates with mitochondria and induces a decrease in mitochondrial SIRT3 levels and mitochondrial biogenesis. We show that SIRT3 downregulation is accompanied by decreased phosphorylation of AMPK and cAMP-response element binding protein (CREB), as well as increased phosphorylation of dynamin-related protein 1 (DRP1), indicative of impaired mitochondrial dynamics. OCR was significantly decreased suggesting a mitochondria respiratory deficit. Interestingly treatment with AMPK agonist 5-aminoimidazole-4carboxamide-1-β-d-ribofuranoside (AICAR) restores SIRT3 expression, improves mitochondrial function, and decreases αsyn oligomer formation in a SIRT3-dependent manner.Conclusions: Together, our findings suggest that pharmacologically increasing SIRT3 levels can counteract αsyninduced mitochondrial dysfunction by reducing αsyn oligomers and normalizing mitochondrial bioenergetics. These data support a protective role for SIRT3 in PD-associated pathways and contribute significant mechanistic insight into the interplay of SIRT3 and αsyn.

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Section: Discussioncontrasting

confidence: 96%

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

Park

Burgess

Faroqi

et al. 2020

Mol Neurodegeneration

136

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“…SIRT3 is the one member of the sirtuin family that exhibits deacetylase activity and is mainly localized to the mitochondria. Regarding to oxidative stress, SIRT3 mainly regulates mitochondrial ROS levels by deacetylating SOD2 and has a positive role in several neurological disorders, including AD, PD and Huntington's disease . And with the downregulated of oxidative stress, the inflammatory and related cytokines can also be normalized.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding to oxidative stress, SIRT3 mainly regulates mitochondrial ROS levels by deacetylating SOD2 and has a positive role in several neurological disorders, including AD, PD and Huntington's disease. [53][54][55][56] And with the downregulated of oxidative stress, the inflammatory and related cytokines can also be normalized. Second, in current studies, our just tested the surgery/anesthesiainduced neuroinflammatory and oxidative stress in hippocampus of mice, but other region in brain (such as prefrontal cortex) and systemic inflammation was not investigated.…”

Section: Effects Of Honokiol On Sirt3/sod2 Signaling Pathwaymentioning

confidence: 99%

SIRT3 activator honokiol ameliorates surgery/anesthesia‐induced cognitive decline in mice through anti‐oxidative stress and anti‐inflammatory in hippocampus

Chen

et al. 2018

CNS Neurosci Ther

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Aims Increasing evidence indicates that neuroinflammatory and oxidative stress play two pivotal roles in cognitive impairment after surgery. Honokiol (HNK), as an activator of Sirtuin3 (SIRT3), has potential multiple biological functions. The aim of these experiments is to evaluate the effects of HNK on surgery/anesthesia‐induced cognitive decline in mice. Methods Adult C57BL/6 mice received a laparotomy under sevoflurane anesthesia and HNK or SIRT3 inhibitor (3‐TYP) treatment. Cognitive function and locomotor activity of mice were evaluated using fear conditioning test and open field test on postoperative 1 and 3 days. Neuronal apoptosis in CA1 and CA3 area of hippocampus was examined using TUNEL assay. And Western blot was applied to measure the expression of pro‐inflammatory cytokines and SIRT3/SOD2 signaling‐associated proteins in hippocampus. Meanwhile, SIRT3 positive cells were calculated by immunohistochemistry. The mitochondrial membrane potential, malondialdehyde (MDA), and mitochondrial radical oxygen species (mtROS) were detected using standard methods. Results Honokiol attenuated surgery‐induced memory loss and neuronal apoptosis, decreased neuroinflammatory response, and ameliorated oxidative damage in hippocampus. Notably, surgery/anesthesia induced an obviously decrease in hippocampal SIRT3 expression, whereas the HNK increased SIRT3 expression and thus decreased the acetylation of superoxide dismutase 2 (SOD2). However, 3‐TYP treatment inhibited the HNK's rescuing effects. Conclusions These results suggested that activation of SIRT3 by honokiol may attenuate surgery/anesthesia‐induced cognitive impairment in mice through regulation of oxidative stress and neuroinflammatory in hippocampus.

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“…Additionally, previous studies have shown that αsyn can also interact with TOM20 (Di Maio et al, 2016), which is required for mitochondrial protein import, and decrease its function. SIRT3 is reported to exist in the cytoplasm in an inactive form and recruited to the mitochondria upon stress (Anamika et al, 2017). It is tempting to speculate that TOM20 plays a role in the translocation of SIRT3 to mitochondria and that αsyn-induced deficit in protein import result in reduced mitochondrial SIRT3 levels thereby initiating the cascade of mitochondrial dysfunction that results in decreased mitochondrial bioenergetics.…”

Section: Discussionmentioning

confidence: 99%

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

Park

Delenclos

Faroqi

et al. 2018

Preprint

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20The sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD + )-dependent en-21 zymes that play a broad role in cellular metabolism and aging. Mitochondrial sirtuin 3 22 (SIRT3) is downregulated in aging and age-associated diseases such as cancer and neuro-23 degeneration and plays a major role in maintaining mitochondrial function and preventing 24 oxidative stress. Mitochondria dysfunction is central to the pathogenesis of Parkinson disease 25 with mutations in mitochondrial-associated proteins such as PINK1 and parkin causing famil-26 ial Parkinson disease. Here, we demonstrate that the presence of alpha-synuclein (αsyn) oli-27 gomers in mitochondria induce a corresponding decrease in mitochondrial SIRT3 activity and 28 decreased mitochondrial biogenesis. We show that SIRT3 downregulation in the presence of 29 αsyn accumulation is accompanied by increased phosphorylation of AMP-activated protein 30 kinase (AMPK) and cAMP-response element binding protein (CREB), as well as increased 31 phosphorylation of dynamin-related protein 1 (DRP1) and decreased levels of optic atrophy 1 32 (OPA1), which is indicative of impaired mitochondrial dynamics. Treatment with the AMPK 33 agonist 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) restores SIRT3 ex-34 pression and activity and improves mitochondrial function by decreasing αsyn oligomer for-35 mation. The accumulation of αsyn oligomers in mitochondria corresponds with SIRT3 down-36 regulation not only in an experimental cellular model, but also in vivo in a rodent model of 37 Parkinson disease, and importantly, in human post mortem brains with neuropathologically 38 confirmed Lewy body disease (LBD). Taken together our findings suggest that pharmacolog-39 ically increasing SIRT3 levels will counteract αsyn-induced mitochondrial dysfunction by 40 normalizing mitochondrial bioenergetics. These data support a protective role for SIRT3 in 41 Parkinson disease-associated pathways and reveals significant mechanistic insight into the 42 interplay of SIRT3 and αsyn. 43 44 45 46 Abbreviations: SIRT3, Sirtuin 3; α-synuclein; αsyn; AMPK, adenosine monophosphate acti-47 vated protein kinase; CREB, cAMP-response element binding protein; DRP1, dynamin-48 related protein 1; OPA1, optic atrophy 1; HO-1, heme oxygenase-1; SOD2, superoxide dis-49 mutase 2; mtROS, mitochondrial reactive oxygen species. 50 51Alpha-synuclein (αsyn) accumulation is believed to be a key step in the pathogenesis of Par-53 kinson's disease and related alpha-synucleinopathies. Despite predominant localization in the 54 cytosol, αsyn is found localized to mitochondria in post-mortem Parkinson's disease brain 55 (Devi et al., 2008). Mitochondrial accumulation of αsyn has been associated with impairment 56 of complex-I dependent respiration, decreased mitochondria membrane potential, and in-57 creased levels of mitochondrial reactive oxygen species (mtROS) in multiple cellular models 58 (Hsu et al., 2000; Devi et al., 2008; Reeve et al., 2015; Ludtmann et al., 2018). The evidence 59 suppo...

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Mitochondrial SIRT3 and neurodegenerative brain disorders

Cited by 72 publications

References 130 publications

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

SIRT3 activator honokiol ameliorates surgery/anesthesia‐induced cognitive decline in mice through anti‐oxidative stress and anti‐inflammatory in hippocampus

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

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