Causal roles of mitochondrial dynamics in longevity and healthy aging

Sharma, Aradhana; Smith, Hannah J.; Yao, Pallas; Mair, William

doi:10.15252/embr.201948395

Cited by 156 publications

(97 citation statements)

References 223 publications

(286 reference statements)

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“…In WM, altered glucose metabolism 45 and impaired oxygen delivery 48 have been shown to contribute to the observed decline. Moreover, mitochondria undergo profound age‐related changes resulting in increased generation of reactive oxygen species, decreased Ca 2+ uptake, and abnormal organelle networks critical to regulating energy metabolism 49,50 . As homeostatic mechanisms become increasingly disrupted, the NGVU is likely to become more vulnerable to these and other cellular events, compromising metabolic activity and ion transport processes coupled to water cycling.…”

Section: Discussionmentioning

confidence: 99%

Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging

Anderson

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et al. 2020

Journal of Neuroimaging

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BACKGROUND AND PURPOSE: Transvascular water exchange plays a key role in the functional integrity of the blood-brain barrier (BBB). In white matter (WM), a variety of imaging modalities have demonstrated age-related changes in structure and metabolism, but the extent to which water exchange is altered remains unclear. Here, we investigated the cumulative effects of healthy aging on WM capillary water exchange. METHODS: A total of 38 healthy adults (aged 36-80 years) were studied using 7T dynamic contrast enhanced MRI. Blood volume fraction (v b) and capillary water efflux rate constant (k po) were determined by fitting changes in the 1 H 2 O longitudinal relaxation rate constant (R 1) during contrast agent bolus passage to a two-compartment exchange model. WM volume was determined by morphometric analysis of structural images. RESULTS: R 1 values and WM volume showed similar trajectories of age-related decline. Among all subjects, v b and k po averaged 1.7 (±0.5) mL/100 g of tissue and 2.1 (±1.1) s −1 , respectively. While v b showed minimal changes over the 40-year-age span of participants, k po declined 0.06 s −1 (ca. 3%) per year (r = −.66; P < .0005), from near 4 s −1 at age 30 to ca. 2 s −1 at age 70. The association remained significant after controlling for WM volume. CONCLUSIONS: Previous studies have shown that k po tracks Na + , K +-ATPase activity-dependent water exchange at the BBB and likely reflects neurogliovascular unit (NGVU) coupled metabolic activity. The age-related decline in k po observed here is consistent with compromised NGVU metabolism in older individuals and the dysregulated cellular bioenergetics that accompany normal brain aging.

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Section: Discussionmentioning

confidence: 99%

Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging

Anderson

Tagge

et al. 2020

Journal of Neuroimaging

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“…Cardiac function and mitochondrial morphology were rescued by Oma1 deletion, which prevented OPA1 cleavage. Defects in mitochondrial dynamics have been associated with ageing [ 199 ] and it is tempting to assume that changes in the expression or activity of such key enzymes as YME1L and Oma1 (particularly as the latter is activated under a variety of stressful conditions) are likely to be involved, although no direct evidence for age-related changes have been reported as yet.…”

Section: Biochemistry Of Mitochondrial Ageingmentioning

confidence: 99%

Intimate Relations—Mitochondria and Ageing

Webb¹,

Sideris²

2020

IJMS

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Mitochondrial dysfunction is associated with ageing, but the detailed causal relationship between the two is still unclear. We review the major phenomenological manifestations of mitochondrial age-related dysfunction including biochemical, regulatory and energetic features. We conclude that the complexity of these processes and their inter-relationships are still not fully understood and at this point it seems unlikely that a single linear cause and effect relationship between any specific aspect of mitochondrial biology and ageing can be established in either direction.

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“…Mitochondria are the main cellular organelles that undergo dynamic changes in response to physiological and pathological changes. These organelles are responsible for driving cell life and death through mitochondrial network structure homeostasis, which is determined by a balance of fission and fusion [1]. Mitochondrial fission is important for maintaining cellular functions, including cellular development and homeostasis, and apoptosis [2,3].…”

Section: Introductionmentioning

confidence: 99%

ROCK1 activation-mediated mitochondrial translocation of Drp1 and cofilin are required for arnidiol-induced mitochondrial fission and apoptosis

Zhang

et al. 2020

J Exp Clin Cancer Res

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Background: Arnidiol is a pentacyclic triterpene diol that has multiple pharmacological activities. However, the apoptotic activities of arnidiol in human cancer cells have not yet been explored, nor has the mechanism by which arnidiol induces apoptosis been examined in depth. Methods: MDA-MB-231 cells and xenografted mice were treated with arnidiol. Mitochondrial fission and apoptosis were determined by immunofluorescence, flow cytometry and related molecular biological techniques. The interaction and colocalization of cofilin and Drp1 was determined by immunoprecipitation and immunofluorescence assays. Results: Arnidiol induces mitochondrial fission and apoptosis through mitochondrial translocation of Drp1 and cofilin. Importantly, the interaction of Drp1 and cofilin in mitochondria is involved in arnidiol-induced mitochondrial fission and apoptosis. Knockdown of either Drp1 or cofilin abrogated arnidiol-induced mitochondrial translocation, interaction of Drp1 and cofilin, mitochondrial fission and apoptosis. Only dephosphorylated Drp1 (Ser637) and cofilin (Ser3) were translocated to the mitochondria. Mutants of Drp1 S637A and cofilin S3A, which mimic the dephosphorylated forms, enhanced mitochondrial fission and apoptosis induced by arnidiol, whereas mutants of Drp1 S637D and cofilin S3E, which mimic the phosphorylated forms, suppressed mitochondrial fission and apoptosis induced by arnidiol. A mechanistic study revealed that ROCK1 activation plays an important role in the arnidiol-mediated Drp1 and cofilin dephosphorylation and mitochondrial translocation, mitochondrial fission, and apoptosis. Conclusions: Our data reveal a novel role of both Drp1 and cofilin in the regulation of mitochondrial fission and apoptosis and suggest that arnidiol could be developed as a potential agent for the treatment of human cancer.

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Causal roles of mitochondrial dynamics in longevity and healthy aging

Cited by 156 publications

References 223 publications

Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging

Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging

Intimate Relations—Mitochondria and Ageing

ROCK1 activation-mediated mitochondrial translocation of Drp1 and cofilin are required for arnidiol-induced mitochondrial fission and apoptosis

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