Metabolic Disturbances in Diseases with Neurological Involvement

Duarte, João M. N.; Schuck, Patrícia Fernanda; Wenk, Gary L.; Ferreira, Gustavo C.

doi:10.14336/ad.2014.0500238

Cited by 38 publications

(39 citation statements)

References 212 publications

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“…Intriguingly, cell non-autonomous effects such as metabolic decline have been observed in these diseases 47 . Therefore, understanding the cell non-autonomous aspects of mitochondrial stress response may allow future control of this protective response, which will have therapeutic potential in the treatment of the symptoms of mitochondrial disorders and neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response

2016

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Neurons have a central role in the systemic coordination of mitochondrial unfolded protein response (UPRmt) and the cell non-autonomous modulation of longevity. However, the mechanism by which the nervous system senses mitochondrial stress and communicates to the distal tissues to induce UPRmt remains unclear. Here we employ the tissue-specific CRISPR-Cas9 approach to disrupt mitochondrial function only in the nervous system of Caenorhabditis elegans, and reveal a cell non-autonomous induction of UPRmt in peripheral cells. We further show that a neural sub-circuit composed of three types of sensory neurons, and one interneuron is required for sensing and transducing neuronal mitochondrial stress. In addition, neuropeptide FLP-2 functions in this neural sub-circuit to signal the non-autonomous UPRmt. Taken together, our results suggest a neuropeptide coordination of mitochondrial stress response in the nervous system.

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Section: Discussionmentioning

confidence: 99%

Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response

2016

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“…The extreme metabolic dysfunction observed in HD patients is far from unique, however. Deleterious changes in metabolism have been reported in a range of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (Cai et al, 2012; Duarte et al, 2014). With neurodegenerative disease, mitochondrial dysfunction in particular manifests across a variety of parameters that include a decline in energy production, impaired tricarboxylic acid cycle activity, decreased electron chain function, and aberrant mitochondrial dynamics (Jenkins et al, 1993; Mochel et al, 2011; Podolsky et al, 1972).…”

Section: Introductionmentioning

confidence: 99%

“…An important consequence of mitochondria stress caused by proteotoxicity is the global alteration of transcription networks associated not only with the regulation of protective chaperones and enzymes (the mitochondrial unfolded protein response, or UPR mt ), but also with metabolism (Cai et al, 2012; Duarte et al, 2014; Nargund et al, 2015). Recent evidence suggests that the transcription factor ATFS-1 is not only capable of upregulating mitochondrial chaperones, proteases, and antioxidant enzymes, but also regulates a large number of genes required for oxidative phosphorylation and glycolysis (Nargund et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

Berendzen

Durieux

Shao

et al. 2016

Cell

213

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SUMMARY During neurodegenerative disease, the toxic accumulation of aggregates and misfolded proteins is often accompanied with widespread changes in peripheral metabolism, even in cells in which the aggregating protein is not present. The mechanism by which the central nervous system elicits a distal reaction to proteotoxic stress remains unknown. We hypothesized that the endocrine communication of neuronal stress plays a causative role in the changes in mitochondrial homeostasis associated with proteotoxic disease states. We find that an aggregation-prone protein expressed in the neurons of C. elegans binds to mitochondria, eliciting a global induction of a mitochondrial-specific unfolded protein response (UPRmt), affecting whole-animal physiology. Importantly, dense core vesicle release and secretion of the neurotransmitter serotonin is required for the signal’s propagation. Collectively, these data suggest the commandeering of a nutrient sensing network to allow for cell-to-cell communication between mitochondria in response to protein folding stress in the nervous system.

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“…These last mutations accumulate in post-mitotic cells with age and amplify the biochemical effects of the former two classes. Accumulation of somatic mtDNA mutations has been shown to be an important factor in the development of PD and Alzheimer's disease (AD) as well as in aging [27]. The role of mtDNA in PD is supported by the analysis of cybrid cells, generated by the fusion of platelets (from control or patient) as mitochondria donor with recipient cells deprived of mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Mitochondrial DNA Profiling of Parkinson’s Disease

Alimazighi

Maponi

Zannotti

et al. 2020

IJMS

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Increasing evidence implicates mitochondrial dysfunction in the etiology of Parkinson’s disease (PD). Mitochondrial DNA (mtDNA) mutations are considered a possible cause and this mechanism might be shared with the aging process and with other age-related neurodegenerative disorders such as Alzheimer’s disease (AD). We have recently proposed a computerized method for mutated mtDNA characterization able to discriminate between AD and aging. The present study deals with mtDNA mutation-based profiling of PD. Peripheral blood mtDNA sequences from late-onset PD patients and age-matched controls were analyzed and compared to the revised Cambridge Reference Sequence (rCRS). The chaos game representation (CGR) method, modified to visualize heteroplasmic mutations, was used to display fractal properties of mtDNA sequences and fractal lacunarity analysis was applied to quantitatively characterize PD based on mtDNA mutations. Parameter β, from the hyperbola model function of our lacunarity method, was statistically different between PD and control groups when comparing mtDNA sequence frames corresponding to GenBank np 5713-9713. Our original method, based on CGR and lacunarity analysis, represents a useful tool to analyze mtDNA mutations. Lacunarity parameter β is able to characterize individual mutation profile of mitochondrial genome and could represent a promising index to discriminate between PD and aging.

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Metabolic Disturbances in Diseases with Neurological Involvement

Cited by 38 publications

References 212 publications

Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response

Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response

Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Mitochondrial DNA Profiling of Parkinson’s Disease

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