Progressive increase in mtDNA 3243A&gt;G heteroplasmy causes abrupt transcriptional reprogramming

Picard, Martin; Zhang, Jiangwen; Hancock, Saege; Derbeneva, Olga; Golhar, Ryan; Golik, Paweł; O’Hearn, Sean F.; Levy, Shawn; Potluri, Prasanth; Lvova, Maria; Dávila, Antonio; Lin, Chengyan; Perín, Juan C.; Rappaport, Eric; Hákonarson, Hákon; Trounce, Ian A.; Procaccio, Vincent; Wallace, Douglas C.

doi:10.1073/pnas.1414028111

Cited by 250 publications

(332 citation statements)

References 52 publications

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“…Second, mitochondria generate reactive metabolic intermediates and ROS, which collectively constitute signals of adaptation, altering chromatin regulation and gene expression within the nucleus (16)(17)(18)(19). Mitochondria therefore could contribute to reported stress-induced epigenetic and transcriptional changes within the hippocampus (8,9,20).…”

Section: Significancementioning

confidence: 99%

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

Picard

McManus

Gray

et al. 2015

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

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216

154

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The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism's multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamicpituitary-adrenal axis, sympathetic adrenal-medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stressresponse signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. stress reactivity | mitochondria | HPA axis | catecholamines | hippocampus R epeated exposure to psychological stress can predispose to disease (1, 2). The underlying mechanisms involve dysregulation of peripheral stress response elements including the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoids (3), the sympathetic adrenal-medullary (SAM) axis and catecholamines (4), systemic inflammation (5), and the "diabetic-like" state of excess circulating glucose and lipids (i.e., metabolic oversupply) promoted by stress hormones (6, 7). In addition, stress leads to neuronal remodeling, which involves changes in brain gene expression, particularly within the hippocampus (8, 9). However, the subcellular factors that modify these systemic responses to stress have not been defined. The objective of this study was to determine if mitochondria mediate physiological stress responses in mice.Mitochondria are symbiotic organelles that contain their own genetic material, the mtDNA, which encodes essential subunits of the respiratory chain complexes I, III, IV, and V. At complex I, electrons derived from energetic substrates (glucose and lipids) enter the respiratory chain and travel to complex IV, where they are combined with oxygen to produce energy in the form of ATP required for life (10). ATP generated inside mitochondria then is ex...

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Section: Significancementioning

confidence: 99%

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

Picard

McManus

Gray

et al. 2015

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

Self Cite

216

154

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“…Based on figures from [26]. mtDNA mutation associated with MELAS [47] has suggested that failure to maintain the cytoplasmic density of wild-type mitochondrial DNA is associated with a pathophysiological response in vitro. However, the data of [26] (neglecting JC-1 measurements) did not strongly constrain the precise relationship between n and v so other scaling relationships are feasible, see Supporting Information Section S2 for further discussion.…”

Section: Cell Physiological Models Coupled To Cell Deathmentioning

confidence: 99%

Mitochondrial heterogeneity, metabolic scaling and cell death

et al. 2017

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Heterogeneity in mitochondrial content has been previously suggested as a major contributor to cellular noise, with multiple studies indicating its direct involvement in biomedically important cellular phenomena. A recently published dataset explored the connection between mitochondrial functionality and cell physiology, where a non-linearity between mitochondrial functionality and cell size was found. Using mathematical models, we suggest that a combination of metabolic scaling and a simple model of cell death may account for these observations. However, our findings also suggest the existence of alternative competing hypotheses, such as a non-linearity between cell death and cell size. While we find that the proposed non-linear coupling between mitochondrial functionality and cell size provides a compelling alternative to previous attempts to link mitochondrial heterogeneity and cell physiology, we emphasise the need to account for alternative causal variables, including cell cycle, size, mitochondrial density and death, in future studies of mitochondrial physiology.

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“…Yeast mutants in different components of the TCA cycle result in differing retrograde responses (46) and comparison of somatic cell hybrids (cybrids) carrying the A3243G mtDNA mutation with cybrids completely lacking mtDNA (ρ 0 cells) showed overlapping but distinct gene expression profiles (47). Moreover, a later study comparing cybrids with increasing levels of the A3243G mtDNA mutation showed markedly different alterations in nuclear gene expression, depending on the severity of mitochondrial dysfunction (48). Taken together, these data suggest that the cellular response to mitochondrial dysfunction is not uniform and adapts to the specific defect and severity of the phenotype.…”

Section: Discussionmentioning

confidence: 86%

Mitochondrial retrograde signaling regulates neuronal function

Cagin

Duncan

Gatt

et al. 2015

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

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Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson’s disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.

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Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming

Cited by 250 publications

References 52 publications

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

Mitochondrial heterogeneity, metabolic scaling and cell death

Mitochondrial retrograde signaling regulates neuronal function

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