Accumulation Of Damaged Mitochondria Research Articles

Gambogic acid and chloroquine synergistically induce cell death via increasing mitochondria damage in human NSCLC cells

AbstractGambogic acid is a natural bioactive compound from the brownish resin of the Garcinia hanburyi trees, which has been shown to induce cell death of cancer cells with a synergistic effect together with other compounds. In the present study, we aim to investigate whether the combination of gambogic and chloroquine, one of the inhibitor of autophagy, could increase cell death in human NSCLC cells. As a result, gambogic acid and chloroquine synergistically suppress the growth of NSCLC cells (CI <0.9). Moreover, the combination of gambogic acid and chloroquine significantly promotes apoptosis than that either alone does. Mechanistically, the results demonstrate that gambogic acid increases PINK1 expression at mRNA and protein level, accompanied with downregulation of Tom20, suggesting the mitophagy process is activated. Both silencing PINK1 and treatment of chloroquine could inhibit mitophagy, therefore disrupting the clearance of damaged mitochondria. Thus, co‐treatment of gambogic acid and chloroquine results in an elevated level of ROS, which facilitates cell death. Taken together, our finding highlights that the synergistically inhibitory effect of gambogic acid and chloroquine on NSCLC cells is associated with the accumulation of mitochondrial damage.

Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis.

Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation. TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin-induced skin fibrosis, bleomycin-induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor β type I receptor (TGFβRΙ). TFAM expression was down-regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down-regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long-term, but not acute, exposure to TGFβ mimicked SSc fibroblasts, with down-regulation of TFAM and accumulation of mitochondrial damage. Down-regulation of TFAM promoted fibroblast activation with up-regulation of fibrosis-relevant Gene Ontology terms in RNA-Seq, partially in a reactive oxygen species-dependent manner. Mice with fibroblast-specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGFβRI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation. Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.

Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis.

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)-induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)-treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain-containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1β-mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

S-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy

S-nitrosylation, a prototypic redox-based posttranslational modification, is frequently dysregulated in disease. S-nitrosoglutathione reductase (GSNOR) regulates protein S-nitrosylation by functioning as a protein denitrosylase. Deficiency of GSNOR results in tumorigenesis and disrupts cellular homeostasis broadly, including metabolic, cardiovascular, and immune function. Here, we demonstrate that GSNOR expression decreases in primary cells undergoing senescence, as well as in mice and humans during their life span. In stark contrast, exceptionally long-lived individuals maintain GSNOR levels. We also show that GSNOR deficiency promotes mitochondrial nitrosative stress, including excessive S-nitrosylation of Drp1 and Parkin, thereby impairing mitochondrial dynamics and mitophagy. Our findings implicate GSNOR in mammalian longevity, suggest a molecular link between protein S-nitrosylation and mitochondria quality control in aging, and provide a redox-based perspective on aging with direct therapeutic implications.

The link of inflammation and neurodegeneration in progressive multiple sclerosis

Progressive multiple sclerosis (MS) is characterized clinically by the accumulation of neurological disability without unequivocal recovery. Understanding the mechanisms that determine entering in this stage of the disease is a great challenge in order to identify potential therapeutic targets. Recent advances in defining more accurately the progressive phenotype of MS, have concluded that differences between primary and secondary progressive forms of disease are relatively quantitative rather than qualitative. In both cases, a large number of molecular and cellular events that might lead to neurodegeneration have been suggested. These include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, age-related disturbances and dysfunctional axonal transport among others. Commonly, these pathological mechanisms have been considered as a result of inflammatory demyelination but a primary degenerative condition has also been argued. It is now clear that both events contribute to the progression of the disease, however their temporal sequence is still a matter of debate. A detailed knowledge of progressive MS pathogenesis will allow to develop effective treatments for both progression and symptom management that should be based on a combination of anti-inflammatory, regenerative and neuroprotective strategies. In this review, we summarize current data and recent hypothesis about pathological forces that drive progression of damage in MS, i.e. cumulative cortical demyelination and neurodegeneration as well as diffuse alterations (microglia activation, axonal injury and atrophy) throughout white and grey matter in the brain and spinal cord. Finally, we discuss the potential of the aforementioned proposed disease mechanisms with regard to developing suitable therapies to halt the progression in MS pathology.

Mitochondrial and sex steroid hormone crosstalk during aging

Decline in circulating sex steroid hormones accompanies several age-associated pathologies which may influence human healthspan. Mitochondria play important roles in biosynthesis of sex steroid hormones, and these hormones can also regulate mitochondrial function. Understanding the cross talk between mitochondria and sex steroid hormones may provide insights into the pathologies associated with aging. The aim of this review is to summarize the current knowledge regarding the interplay between mitochondria and sex steroid hormones during the aging process. The review describes the effect of mitochondria on sex steroid hormone production in the gonads, and then enumerates the contribution of sex steroid hormones on mitochondrial function in hormone responsive cells. Decline in sex steroid hormones and accumulation of mitochondrial damage may create a positive feedback loop that contributes to the progressive degeneration in tissue function during aging. The review further speculates whether regulation between mitochondrial function and sex steroid hormone action can potentially influence healthspan.

Insufficient autophagy relates to mitochondrial dysfunction, organ failure and adverse outcome in an animal model of critical illness

Increasing evidence implicates mitochondrial dysfunction in the pathogenesis of critical illness-induced multiple organ failure. We previously demonstrated that prevention of hyperglycemia limits mitochondrial damage in vital organs [1,2], thereby reducing morbidity and mortality [3]. We now hypothesize that inadequate activation of mitochondrial repair processes (mitochondrial clearance by autophagy, mitochondrial fusion and fission, and biogenesis) may contribute to accumulation of mitochondrial damage, persistence of organ failure and adverse outcome of critical illness.