The role of mitochondrial genome abundance in Alzheimer's disease

Harerimana, Nadia V.; Paliwali, Devashi; Romero‐Molina, Carmen; Bennett, David A.; Pa, Judy; Goate, Alison; Swerdlow, Russell H.; Andrews, Shea J.

doi:10.1002/alz.12812

Cited by 8 publications

(5 citation statements)

References 88 publications

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“…"Cellular response to reactive oxygen species" is related to the reduction of bioenergetics of mitochondria. 19,20 The above results suggest that N-phosphorylation plays an important role in Alzheimer's disease.…”

Section: ■ and Discussionmentioning

confidence: 77%

“…Further biological process analysis of N-phosphorylation proteins showed that “brain development”, “cellular response to reactive oxygen species”, “microtubule cytoskeleton organization”, and “peptidyl-serine phosphorylation” specifically occurs in a 5 × FAD mouse. “Cellular response to reactive oxygen species” is related to the reduction of bioenergetics of mitochondria. , The above results suggest that N-phosphorylation plays an important role in Alzheimer’s disease.…”

Section: Resultsmentioning

confidence: 93%

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Efficient Enrichment Method for N-Phosphorylation Peptides in Mouse Brain Tissue

Pan

Wang

et al. 2023

J. Am. Soc. Mass Spectrom.

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In addition to O-phosphorylation, protein N-phosphorylation was proven to play important roles in multiple biological processes. Although affinity methods were developed for the enrichment of N-phosphorylation peptides in cells, it was still difficult to enrich N-phosphorylation peptides in tissue due to its complexity. In this study, we established a workflow for the identification of N-phosphorylation peptides in mouse brain tissue by direct enrichment in high concentration urea. In total, 989 N-phosphorylation sites were obtained using 0.5 M urea as enrichment buffer. Among all identified N-phosphorylation sites, the localization probability over 0.75 was as high as 80%, suggesting the reliability of the method. Furthermore, the sequence motif analysis and gene ontology analysis results showed a good match to previous studies. The method was successfully used for N-phosphorylation analysis of mouse hippocampus from Alzheimer’s disease model, and 533 N-phosphorylation sites were identified in 5 × FAD mouse hippocampus tissue. Biological process analysis results showed that “brain development”, “cellular response to reactive oxygen species”, “microtubule cytoskeleton organization”, and “peptidyl-serine phosphorylation” were especially enriched in 5 × FAD mouse. It is suggested that N-phosphorylation may be related to Alzheimer’s disease in these aspects.

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Section: ■ and Discussionmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 93%

Efficient Enrichment Method for N-Phosphorylation Peptides in Mouse Brain Tissue

Pan

Wang

et al. 2023

J. Am. Soc. Mass Spectrom.

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“…Neuronal cells depend on appropriate mitochondrial distribution to maintain function and neural connections. Aberrant distribution alters synaptic activities while inadequate neuronal-mitochondrial populations contribute to neuronal damage observed in AD (Harerimana et al, 2022). To determine if the presence of abnormally phosphorylated tau could impact mitochondrial distribution and population, cells were transfected with mito-mCherry and GFP tagged-T4 or the different phosphomimetic forms of tau.…”

Section: Resultsmentioning

confidence: 99%

Site-specific phosphorylation of tau impacts mitochondrial biology and response to stressors

Isei

Girardi

Rodwell-Bullock

et al. 2023

Preprint

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Phosphorylation of tau at sites associated with Alzheimer's disease (AD) likely plays a role in the disease progression. Mitochondrial impairment, correlating with increased presence of phosphorylated tau, has been identified as a contributing factor to neurodegenerative processes in AD. However, how tau phosphorylated at specific sites impacts mitochondrial function has not been fully defined. We examined how AD-relevant phosphomimetics of tau impact selected aspects of mitochondrial biology. To mimic phosphorylation at AD-associated sites, the Ser/Thr sites in wild-type GFP tagged-tau (T4) were converted to glutamic acid (E) to make pseudophosphorylated GFP tagged-Ser-396/404 (2EC) and GFP tagged-Thr-231/Ser-235 (2EM) constructs. These constructs were expressed in neuronal HT22 cells and their impact on specific mitochondrial functions and responses to stressors were measured. Phosphomimetic tau altered mitochondrial distribution. Specifically, mitochondria accumulated in the soma of cells expressing either 2EC or 2EM, and neurite-like extensions in 2EC cells were shorter. Additionally, ATP levels were reduced in both 2EC and 2EM expressing cells, and ROS production increased in 2EC cells during oxidation of succinate when compared to T4 expressing cells. Thapsigargin reduced mitochondrial membrane potential (Ψm) and increased ROS production in both 2EC and 2EM cells relative to T4 cells, with no significant difference in the effects of rotenone. These results show that tau phosphorylation at specific AD-relevant epitopes negatively affects mitochondria, with the extent of dysfunction and stress response varying according to the sites of phosphorylation. Altogether, these findings extend our understanding of potential mechanisms whereby phosphorylated tau promotes mitochondria dysfunction in tauopathies, including AD.

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“…Neuronal cells depend on appropriate mitochondrial distribution to maintain function and neural connections. Aberrant distribution alters synaptic activities while inadequate neuronal–mitochondrial populations contribute to neuronal damage observed in AD (Harerimana et al, 2023). To determine if the presence of abnormally phosphorylated tau could impact mitochondrial distribution and population, cells were transfected with mito‐mCherry and GFP‐tagged T4 or the different phosphomimetic forms of tau.…”

Section: Resultsmentioning

confidence: 99%

Site‐specific phosphorylation of tau impacts mitochondrial function and response to stressors

Isei,

Girardi,

Rodwell‐Bullock

et al. 2023

Journal of Neurochemistry

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Phosphorylation of tau at sites associated with Alzheimer's disease (AD) likely plays a role in the disease progression. Mitochondrial impairment, correlating with increased presence of phosphorylated tau, has been identified as a contributing factor to neurodegenerative processes in AD. However, how tau phosphorylated at specific sites impacts mitochondrial function has not been fully defined. We examined how AD‐relevant phosphomimetics of tau impact selected aspects of mitochondrial biology. To mimic phosphorylation at AD‐associated sites, the serine/threonine (Ser/Thr) sites in wild‐type green fluorescent protein (GFP)‐tagged tau (T4) were converted to glutamic acid (E) to make pseudo‐phosphorylated GFP‐tagged Ser‐396/404 (2EC) and GFP‐tagged Thr‐231/Ser‐235 (2EM) constructs. These constructs were expressed in immortalized mouse hippocampal neuronal cell lines, and their impact on specific mitochondrial functions and responses to stressors were measured. Phosphomimetic tau altered mitochondrial distribution. Specifically, mitochondria accumulated in the soma of cells expressing either 2EC or 2EM and neurite‐like extensions in 2EC cells were shorter. Additionally, adenosine triphosphate levels were reduced in both 2EC‐ and 2EM‐expressing cells, and reactive oxygen species (ROS) production increased in 2EC cells during oxidation of succinate when compared to T4‐expressing cells. Thapsigargin reduced mitochondrial membrane potential and increased ROS production in both 2EC and 2EM cells relative to T4 cells, with no significant difference in the effects of rotenone. These results show that tau phosphorylation at specific AD‐relevant epitopes negatively affects mitochondria, with the extent of dysfunction and stress response varying according to the sites of phosphorylation. Altogether, these findings show that phosphorylated tau increases mitochondrial susceptibility to stressors and extend our understanding of potential mechanisms whereby phosphorylated tau promotes mitochondria dysfunction in tauopathies, including AD.image

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The role of mitochondrial genome abundance in Alzheimer's disease

Cited by 8 publications

References 88 publications

Efficient Enrichment Method for N-Phosphorylation Peptides in Mouse Brain Tissue

Efficient Enrichment Method for N-Phosphorylation Peptides in Mouse Brain Tissue

Site-specific phosphorylation of tau impacts mitochondrial biology and response to stressors

Site‐specific phosphorylation of tau impacts mitochondrial function and response to stressors

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