Mitochondrial Dysfunction Induces Sarm1-Dependent Cell Death in Sensory Neurons

Summers, Daniel W.; DiAntonio, X Aaron; Milbrandt, Jeffrey

doi:10.1523/jneurosci.0877-14.2014

Cited by 168 publications

(179 citation statements)

References 56 publications

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“…Neurons are especially susceptive to mitochondrial dysfunction. Progressive ROS accumulation in neurons can exacerbate protein aggregation, cell death, and result in onset of neurodegeneration [20]. Recently, it is reported that ROS originated from [4].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

et al. 2015

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Emerging data suggests that mitochondrial dysfunction is prominently involved in Alzheimer disease (AD) progression. Sirtuin-3 (Sirt3) is a member of the sirtuin family of nicotinamide adenine dinucleotide dependent deacetylases that regulates a variety of mitochondrial functions and suppresses mitochondria-related physiology. Here, we determined sirt3 expression in a mouse model of AD. Spatial learning and memory were tested by Morris water maze in APP/PS1 double transgenic mice. The expression of sirt3 was assayed by real-time quantitative PCR and western blotting. Age-and gender-matched wild-type (WT) littermates were used as controls. Cortical sirt3 localization was assessed using immunohistochemistry. The expression of sirt3 mRNA was significantly lower in the cortex of APP/PS1 double transgenic mice than in WT littermates (0.83 ± 0.24 vs. 1.10 ± 0.21, P < 0.05). A comparable reduction was found in sirt3 protein levels using western blotting. The ratio of mean optical density (MOD) of total sirt3/β-actin in the cortex was 0.77 ± 0.11 in APP/PS1 double transgenic mice and 1.34 ± 0.17 in the WT littermates (P < 0.01). Immunohistochemistry showed the same change as western blotting. The ratio of MOD of integral optical density/total area in APP/PS1 and WT littermates was 0.58 ± 0.02 and 0.71 ± 0.05 (P < 0.01). These data show that sirt3 was depleted in APP/PS1 double transgenic mice. The results suggest that mitochondrial sirt3 might participate in the development of AD via mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

et al. 2015

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“…Furthermore, SARM1 (K597E) expression suppressed axon degeneration and cell death after treatment with carbonyl cyanide 3-chlorophenylhydrazone (CCCP) (Fig. 5 C and D), a mitochondrial toxin that stimulates SARM1-dependent axon degeneration and cell death (7). In contrast, SARM1 (K597E) did not suppress cell death in response to trophic factor withdrawal (Fig.…”

Section: Mutant Sarm1 (K597e) Acts As a Dominant Negative And Blocksmentioning

confidence: 93%

“…Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5,6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen glucose deprivation, and viral infection (7)(8)(9)(10). Activated SARM1 can induce cell death independent of other known programmed cell death programs in a pathway termed sarmoptosis.…”

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confidence: 99%

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Summers

Gibson

DiAntonio

et al. 2016

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

121

125

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Axon injury in response to trauma or disease stimulates a selfdestruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD + and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD + loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD + loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD + loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.A xon degeneration in response to injury or disease is a hallmark of neurological disorders of the peripheral and central nervous systems. Akin to programmed cell death pathways, such as apoptosis, axon injury in response to disease or trauma stimulates a local signaling cascade that executes destruction of the injured axon segment (1). Despite growing attention, the molecular details of this prodegenerative cascade are still unclear. A more substantial understanding of the molecular factors that participate in this axon destructive process will likely provide new therapeutic strategies for peripheral neuropathies and other neurodegenerative conditions.Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2, 3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4). Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5, 6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen gluc...

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“…Several key mitochondrial functions rely on the potential across the mitochondrial inner membrane. Loss of membrane potential is associated with mitochondrial fragmentation and impaired trafficking (4), and can potentially activate cell death pathways (5). To safeguard against these deleterious outcomes, eukaryotic cells have developed quality control mechanisms to monitor the membrane potential of resident mitochondria and selectively eliminate depolarized organelles through mitophagy.…”

mentioning

confidence: 99%

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy

Moore

Holzbaur

2016

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

291

266

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Mitochondria play an essential role in maintaining cellular homeostasis. The removal of damaged or depolarized mitochondria occurs via mitophagy, in which damaged mitochondria are targeted for degradation via ubiquitination induced by PTEN-induced putative kinase 1 (PINK1) and Parkin. Mitophagy receptors, including optineurin (OPTN), nuclear dot 52 kDa protein (NDP52), and Tax1-binding protein 1 (TAX1BP1), are recruited to mitochondria via ubiquitin binding and mediate autophagic engulfment through their association with microtubule-associated protein light chain 3 (LC3). Here, we use livecell imaging to demonstrate that OPTN, NDP52, and TAX1BP1 are recruited to mitochondria with similar kinetics following either mitochondrial depolarization or localized generation of reactive oxygen species, leading to sequestration by the autophagosome within ∼45 min after insult. Despite this corecruitment, we find that depletion of OPTN, but not NDP52, significantly slows the efficiency of sequestration. OPTN is phosphorylated by the kinase TANK-binding kinase 1 (TBK1) at serine 177; we find that TBK1 is corecruited with OPTN to depolarized mitochondria. Inhibition or depletion of TBK1, or expression of amyotrophic lateral sclerosis (ALS)-associated OPTN or TBK1 mutant blocks efficient autophagosome formation. Together, these results indicate that although there is some functional redundancy among mitophagy receptors, efficient sequestration of damaged mitochondria in response to mitochondrial stress requires both TBK1 and OPTN. Notably, ALSlinked mutations in OPTN and TBK1 can interfere with mitophagy, suggesting that inefficient turnover of damaged mitochondria may represent a key pathophysiological mechanism contributing to neurodegenerative disease.itochondria form interconnected networks that continuously remodel in response to shifting cellular needs (1). These dynamic networks serve as hubs for diverse cellular functions, including aerobic metabolism, calcium homeostasis (2), and redox signaling (3). Several key mitochondrial functions rely on the potential across the mitochondrial inner membrane. Loss of membrane potential is associated with mitochondrial fragmentation and impaired trafficking (4), and can potentially activate cell death pathways (5). To safeguard against these deleterious outcomes, eukaryotic cells have developed quality control mechanisms to monitor the membrane potential of resident mitochondria and selectively eliminate depolarized organelles through mitophagy.In mitophagy, damaged mitochondria are recognized and then sequestered by a double-membrane autophagosome, leading to selective degradation. Regulation of this process involves the ubiquitin kinase PTEN-induced putative kinase 1 (PINK1) (6) and the E3-ubiquitin ligase Parkin (7). Specifically, PINK1 accumulates on the surface of depolarized mitochondria, where it phosphorylates ubiquitin on local outer membrane proteins, resulting in the recruitment of Parkin (7-11). Parkin, in turn, modifies additional mitochondrial outer membrane proteins...

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Mitochondrial Dysfunction Induces Sarm1-Dependent Cell Death in Sensory Neurons

Cited by 168 publications

References 56 publications

Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy

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Mitochondrial Dysfunction Induces Sarm1-Dependent Cell Death in Sensory Neurons

Cited by 168 publications

References 56 publications

Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy

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SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation