Integrating multiple aspects of mitochondrial dynamics in neurons: Age-related differences and dynamic changes in a chronic rotenone model

AbstractChronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

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Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Cells ◽

10.3390/cells9030598 ◽

2020 ◽

Vol 9 (3) ◽

pp. 598 ◽

Cited By ~ 9

Author(s):

Anna Picca ◽

Riccardo Calvani ◽

Hélio José Coelho-Junior ◽

Francesco Landi ◽

Roberto Bernabei ◽

...

Keyword(s):

Quality Control ◽

Mitochondrial Dysfunction ◽

Mitochondrial Dynamics ◽

Mitochondrial Quality Control ◽

Membrane Contact Sites ◽

Contact Sites ◽

Age Related ◽

Bidirectional Communication ◽

Membrane Contact ◽

Organelle Membrane

Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson’s disease as a prototypical geroscience condition.

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Moderation of mitochondrial respiration mitigates metabolic syndrome of aging

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1917948117 ◽

2020 ◽

Vol 117 (18) ◽

pp. 9840-9850 ◽

Cited By ~ 1

Author(s):

Mojdeh Tavallaie ◽

Ramouna Voshtani ◽

Xinxian Deng ◽

Yixue Qiao ◽

Faqin Jiang ◽

...

Keyword(s):

Metabolic Syndrome ◽

Mitochondrial Respiration ◽

Mitochondrial Dynamics ◽

Atp Synthesis ◽

Control Group ◽

Standard Diet ◽

Ros Production ◽

Metabolic Complications ◽

Age Related ◽

Mitochondrial Functions

Deregulation of mitochondrial dynamics leads to the accumulation of oxidative stress and unhealthy mitochondria; consequently, this accumulation contributes to premature aging and alterations in mitochondria linked to metabolic complications. We postulate that restrained mitochondrial ATP synthesis might alleviate age-associated disorders and extend healthspan in mammals. Herein, we prepared a previously discovered mitochondrial complex IV moderate inhibitor in drinking water and orally administered to standard-diet-fed, wild-type C57BL/6J mice every day for up to 16 mo. No manifestation of any apparent toxicity or deleterious effect on studied mouse models was observed. The impacts of an added inhibitor on a variety of mitochondrial functions were analyzed, such as respiratory activity, mitochondrial bioenergetics, and biogenesis, and a few age-associated comorbidities, including reactive oxygen species (ROS) production, glucose abnormalities, and obesity in mice. It was found that mitochondrial quality, dynamics, and oxidative metabolism were greatly improved, resulting in lean mice with a specific reduction in visceral fat plus superb energy and glucose homeostasis during their aging period compared to the control group. These results strongly suggest that a mild interference in ATP synthesis through moderation of mitochondrial activity could effectively up-regulate mitogenesis, reduce ROS production, and preserve mitochondrial integrity, thereby impeding the onset of metabolic syndrome. We conclude that this inhibitory intervention in mitochondrial respiration rectified the age-related physiological breakdown in mice by protecting mitochondrial function and markedly mitigated certain undesired primary outcomes of metabolic syndrome, such as obesity and type 2 diabetes. This intervention warrants further research on the treatment of metabolic syndrome of aging in humans.

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Targeting Mitochondrial Network Architecture in Down Syndrome and Aging

International Journal of Molecular Sciences ◽

10.3390/ijms21093134 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3134 ◽

Cited By ~ 5

Author(s):

Nunzia Mollo ◽

Rita Cicatiello ◽

Miriam Aurilia ◽

Roberta Scognamiglio ◽

Rita Genesio ◽

...

Keyword(s):

Down Syndrome ◽

Network Architecture ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Mammalian Target Of Rapamycin ◽

Protective Effects ◽

Mitochondrial Network ◽

Factors Affecting ◽

Age Related ◽

Underlying Causes

Mitochondria are organelles that mainly control energy conversion in the cell. In addition, they also participate in many relevant activities, such as the regulation of apoptosis and calcium levels, and other metabolic tasks, all closely linked to cell viability. Functionality of mitochondria appears to depend upon their network architecture that may dynamically pass from an interconnected structure with long tubular units, to a fragmented one with short separate fragments. A decline in mitochondrial quality, which presents itself as an altered structural organization and a function of mitochondria, has been observed in Down syndrome (DS), as well as in aging and in age-related pathologies. This review provides a basic overview of mitochondrial dynamics, from fission/fusion mechanisms to mitochondrial homeostasis. Molecular mechanisms determining the disruption of the mitochondrial phenotype in DS and aging are discussed. The impaired activity of the transcriptional co-activator PGC-1α/PPARGC1A and the hyperactivation of the mammalian target of rapamycin (mTOR) kinase are emerging as molecular underlying causes of these mitochondrial alterations. It is, therefore, likely that either stimulating the PGC-1α activity or inhibiting mTOR signaling could reverse mitochondrial dysfunction. Evidence is summarized suggesting that drugs targeting either these pathways or other factors affecting the mitochondrial network may represent therapeutic approaches to improve and/or prevent the effects of altered mitochondrial function. Overall, from all these studies it emerges that the implementation of such strategies may exert protective effects in DS and age-related diseases.

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To unite or divide: mitochondrial dynamics in the murine outer retina that preceded age related photoreceptor loss

Oncotarget ◽

10.18632/oncotarget.5614 ◽

2015 ◽

Vol 6 (29) ◽

pp. 26690-26701 ◽

Cited By ~ 16

Author(s):

Jaimie Hoh Kam ◽

Glen Jeffery

Keyword(s):

Mitochondrial Dynamics ◽

Outer Retina ◽

Age Related

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Dynamic Changes of High-Sensitivity Troponin T Concentration During Infancy: Clinical Implications

Physiological Research ◽

10.33549/physiolres.934453 ◽

2021 ◽

pp. 27-32 ◽

Cited By ~ 1

Author(s):

P JEHLICKA ◽

D RAJDL ◽

E SLADKOVA ◽

A SYKOROVA ◽

J SYKORA

Keyword(s):

Cardiac Troponin ◽

Troponin T ◽

Dominant Role ◽

Adult Population ◽

Plasma Concentrations ◽

Reference Intervals ◽

Postnatal Life ◽

Cardiac Troponin T ◽

Dynamic Changes ◽

Age Related

Cardiac troponin T determination plays a dominant role in diagnosis of myocardial pathologies. Despite generally accepted use of high-sensitive cardiac troponin T assays (hscTnT) and clearly defined cut-off limit in adults, the uncertainty persists in infants. The aim of this study was to assess plasmatic concentrations of hscTnT and describe sequential age-related dynamic changes of hscTnT in healthy infants and toddlers. Seventy-eight children (52 males/26 females) from Czech Republic aged 44 to 872 days (median, interquartile range 271; 126 to 486 days) were consecutively enrolled in the single-center, prospective observational study. Plasma concentrations of hscTnT were analyzed by the electrochemiluminescent method, age-related reference intervals were calculated using the polynominal regression model. Amongst the study population (n=78), the upper limit of hscTnT concentration defined as the 99th percentile was calculated. The 99th percentile with 95 % confidence interval at the end of 2nd, 3rd, 4th, 5th, 6th and 7th month of postnatal life were: 81 (40.6 to 63.6), 61 (36.0 to 55.3), 47 (31.9 to 48.3), 37 (28.1 to 42.3), 30 (24.7 to 37.2) and 25 (21.5 to 32.7) ng/l, respectively. Concentration of adults 99th percentile (14 ng/l) was achieved approximately at 1 year of postnatal life. Statistically significant negative correlation of hscTnT concentration with age (r=-0.81, p<0.001) was found. Significant gender differences were not found (p>0.07). The study revealed substantially increased reference intervals of hscTnT levels in infants when compared with adult population. Based on our preliminary results, the age-related interpretation of hscTnT plasmatic concentration is recommended.

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EPEN-11. TUMOR DIFFERENTIATION IMPACTS THE BIOLOGY OF RECURRENCE IN CHILDHOOD POSTERIOR FOSSA EPENDYMOMA

Neuro-Oncology ◽

10.1093/neuonc/noab090.061 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i15-i16

Author(s):

Andrew Donson ◽

Timothy Ritzmann ◽

Nicholas Willard ◽

Andrea Griesinger ◽

Vladimir Amani ◽

...

Keyword(s):

Neoplastic Cell ◽

Cellular Biology ◽

Cell Subpopulation ◽

Dynamic Changes ◽

Subtype Assignment ◽

Age Related ◽

Rnaseq Data ◽

Frequent Event ◽

Made In

Abstract Ependymoma (EPN) of childhood is curable in only 50% of cases, with recurrences in the remainder that are refractory to treatment. In recent years significant advances have been made in understanding the molecular and cellular biology of EPN. Recent studies show that PFA subgroup EPN are comprised of multiple neoplastic subpopulations that show undifferentiated, differentiated and mesenchymal characteristics. These studies focused on tumor at presentation, with recurrent EPN being less well understood. In the present longitudinal study we examine changes in neoplastic cell heterogeneity in serial presentations of PFA EPN using deconvolution (Cibersort) of bulk RNAseq data. Analysis of a cohort of 48 PFA EPN presenting at Children’s Colorado showed survival and PFA1/PFA2 subtype assignment was associated with the proportion of individual neoplastic subpopulations as determined by deconvolution. Tumors that subsequently regrew had a significantly higher estimated proportion of undifferentiated EPN cells (UEC) at presentation, than those that were non-recurrent after 5 years follow-up. This outcome association potentially age related, as UEC proportions are significantly higher in PFA arising in children < 1 year old who have a particularly poor prognosis. Changes in PFA neoplastic subpopulations at recurrence was performed in two cohorts of patients from Children’s Colorado (n=23) and Nottingham, UK (n=15). As a whole, no subpopulation proportion was significantly changed at recurrence. However, separation of PFA into subtypes PFA1 and PFA2 revealed an increase in the proportion of the cilia-differentiated EPN cell subpopulation is more frequent event in PFA1 (15/24), and rare in PFA2 (2/11). Changes in other neoplastic subpopulations at recurrence were smaller and only seen in PFA1, both UEC and mesenchymal subpopulations being lower at recurrence. In summary, only PFA1 showed dynamic changes in neoplastic subpopulation proportions at recurrence, with potential impacts on transcriptomic based-subgroup assignment, whereas PFA2 proportions remained largely stable.

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Mitochondrial Aging and Age-Related Dysfunction of Mitochondria

BioMed Research International ◽

10.1155/2014/238463 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 115

Author(s):

Dimitry A. Chistiakov ◽

Igor A. Sobenin ◽

Victor V. Revin ◽

Alexander N. Orekhov ◽

Yuri V. Bobryshev

Keyword(s):

Mitochondrial Function ◽

Antioxidant Defense ◽

Mitochondrial Dynamics ◽

Oxidative Capacity ◽

Ros Generation ◽

Atp Production ◽

Age Related ◽

Related Phenotype ◽

Age Dependent ◽

Aged Subjects

Age-related changes in mitochondria are associated with decline in mitochondrial function. With advanced age, mitochondrial DNA volume, integrity and functionality decrease due to accumulation of mutations and oxidative damage induced by reactive oxygen species (ROS). In aged subjects, mitochondria are characterized by impaired function such as lowered oxidative capacity, reduced oxidative phosphorylation, decreased ATP production, significant increase in ROS generation, and diminished antioxidant defense. Mitochondrial biogenesis declines with age due to alterations in mitochondrial dynamics and inhibition of mitophagy, an autophagy process that removes dysfunctional mitochondria. Age-dependent abnormalities in mitochondrial quality control further weaken and impair mitochondrial function. In aged tissues, enhanced mitochondria-mediated apoptosis contributes to an increase in the percentage of apoptotic cells. However, implementation of strategies such as caloric restriction and regular physical training may delay mitochondrial aging and attenuate the age-related phenotype in humans.

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Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00936.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. H459-H476 ◽

Cited By ~ 111

Author(s):

Emanuele Marzetti ◽

Anna Csiszar ◽

Debapriya Dutta ◽

Gauthami Balagopal ◽

Riccardo Calvani ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Cardiovascular System ◽

Current Knowledge ◽

Mitochondrial Dynamics ◽

Late Life ◽

Age Related ◽

Functional Consequences ◽

Cardiovascular Aging ◽

The Life Course

Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The age-related accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD.

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