Cytosolic malate dehydrogenase regulates senescence in human fibroblasts

Lee, Seungmin; Dho, So Hee; Ju, Sung-Kyu; Maeng, Jin-Soo; Kim, Jeong‐Yoon; Kwon, Ki‐Sun

doi:10.1007/s10522-012-9397-0

Cited by 55 publications

(44 citation statements)

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“…NADH reducing equivalents are transferred across the mitochondrial membrane by the malate-aspartate shuttle (Lehninger et al, 2013), and depletion of the shuttle component malate dehydrogenase-1 induces a senescence arrest (Lee et al, 2012). Aminooxyacetate (AOA) inhibits the shuttle, lowering the cytosolic, but not mitochondrial, NAD+/NADH ratio (López-Alarcón and Eboli, 1986).…”

Section: Resultsmentioning

confidence: 99%

“…While mitochondria oxidize NADH generated by the tricarboxylic acid (TCA) cycle or fatty acid oxidation, they also oxidize the cytosolic NAD +/NADH pool through the α-glycerophosphate and malate-aspartate shuttles (Houtkooper et al, 2010). Inhibition of the latter by depletion of malate dehydrogenase lowers the NAD+/NADH ratio and induces a senescence arrest (Lee et al, 2012), suggesting that elevated cytoplasmic NADH can drive cells into senescence. Notably, NAD+ declines with age in several tissues (Braidy et al, 2011; Gomes et al, 2013; Stein and Imai, 2014; Yoshino et al, 2011), linking NAD to both senescence and aging.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

et al. 2016

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SUMMARY Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

et al. 2016

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“…An additional role for malate in preventing senescence derives from studies that entail an inhibition of malate dehydrogenase 1 (MDH1), a component of the malate-aspartate shuttle, which transfers reducing equivalents of NADH from the cytosol to the mitochondrial matrix (Lee et al, 2012). Like the malic enzymes, MDH1 levels and activity decline in senescent cells, and MDH1 depletion induces a senescence response.…”

Section: General Metabolic Features Of Senescent Cellsmentioning

confidence: 99%

From Ancient Pathways to Aging Cells—Connecting Metabolism and Cellular Senescence

2016

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Cellular senescence is a complex stress response that permanently arrests the proliferation of cells at risk for oncogenic transformation. However, senescent cells can also drive phenotypes associated with aging. Although the senescence-associated growth arrest prevents the development of cancer and the metabolism of cancer cells has been studied in depth, the metabolic causes and consequences of cellular senescence were largely unexplored until recently. New findings reveal key roles for several aspects of cellular metabolism in the establishment and control of senescent phenotypes. These discoveries have important implications for both cancer and aging. In this review, we highlight some of the recent links between metabolism and phenotypes that are commonly associated with senescent cells.

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“…Potential mechanisms of mitochondrial dysfunction-induced senescence include enhanced levels of ROS, sustained activation of AMPK, and alterations of the NAD + /NADH ratio (141)(142)(143). Importantly, NAD has been linked to both senescence and aging, and mitochondrial sirtuins such as the NAD-dependent proteins SIRT3 and SIRT5 can suppress senescence and modulate SASP (18,140).…”

Section: Metabolic Dysregulation As a Convergent Event In The Aging Cellmentioning

confidence: 99%

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

176

169

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One of the most remarkable medical accomplishments in the last century has been the increasing longevity of the human population. A decrease in birth rates, accompanied by a reduction in mortality among the elderly population, has collectively increased the percentage of the aged population, particularly in developed countries. Globally, it is estimated that the proportion of the population over the age of 60 will increase from 11% to 22% by 2050, and 28% by 2100. Currently, 18% of the US population is over 60 years of age (57 million), which is predicted to rise to 27% (107 million) in 2050 and up to 31% (149 million) by 2100 (1). The aging population has propelled an increase in the overall prevalence of chronic conditions. Several lung diseases, including acute lung injury and asthma, and some infectious diseases, such as pneumonia, increase in severity and mortality with age. Additionally, there has been a significant increase in incidence of chronic lung diseases -including chronic obstructive pulmonary disease, most forms of lung cancer, and idiopathic pulmonary fibrosis (IPF) -resulting in aging-related increases in prevalence.IPF is the most common form of idiopathic interstitial lung diseases. Its overall incidence in the US is 7 to 17 per 100,000 persons with a prevalence between 13.2 and 63 per 100,000 persons (2). A 1996 study initially demonstrated a higher incidence and prevalence of IPF in patients over 65 (3). These observations were confirmed more recently by Raghu et al. (4) and others, using both broad and narrow case-finding criteria for IPF diagnosis. These studies estimated that in the US, the prevalence of IPF increases with age, ranging from 4 per 100,000 for population aged between 18 and 34 years old to 227.2 per 100,000 among those 75 or older (4). This aging-related increase in cumulative incidence and prevalence of IPF has been corroborated by several studies that include populations in Europe and Asia (5-9). Accordingly, the median age at diagnosis of sporadic IPF ranges between 50 and 85 years old, and patients younger than 50 are more commonly associated with familial, rather than sporadic, forms of the disease (2). Mortality rates from IPF are steadily increasing worldwide, and a positive association has also been observed with advanced age (10). Examination of US government health insurance data for people aged 65 and older shows an increasing prevalence of IPF among older age groups (11). These studies confirm the growing concern that aging, and consequently age-related diseases, will drive up health care expenditures. As the elderly population in developed countries is expected to double in the next 25 years, there is an urgent need to understand the pathogenesis of IPF and develop interventions to attenuate or reverse lung fibrosis. The physiology of aging and the lungEvolutionary theories of aging include the concept of selection shadow that permits the accumulation of mutations with late deleterious effects, and the theory of antagonistic pleiotropy, which supports the sele...

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Cytosolic malate dehydrogenase regulates senescence in human fibroblasts

Cited by 55 publications

References 50 publications

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

From Ancient Pathways to Aging Cells—Connecting Metabolism and Cellular Senescence

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

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