Quality control of mitochondria during aging: Is there a good and a bad side of mitochondrial dynamics?

Figge, Marc Thilo; Osiewacz, Heinz D.; Reichert, Andreas S.

doi:10.1002/bies.201200125

Cited by 26 publications

(13 citation statements)

References 78 publications

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“…The importance of this flexibility has been recently suggested from mathematical modeling in which mitochondrial dynamics, mitochondrial biogenesis, mitophagy, and mitochondrial damage were analyzed. This study revealed that the deceleration of fission and fusion appears to be beneficial for an organism when mitochondrial damage passed specific threshold levels 36 38 . The elucidation of the underlying mechanisms controlling such flexibility including the sensing of impairments and imbalances and the induction of potential compensatory mechanisms certainly holds the key for understanding the complex network of pathways involved in lifespan control, aging and the development of mitochondrial diseases.…”

Section: Discussionmentioning

confidence: 85%

Simultaneous impairment of mitochondrial fission and fusion reduces mitophagy and shortens replicative lifespan

Bernhardt

Müller

Reichert

et al. 2015

Sci Rep

Self Cite

102

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Aging of biological systems is accompanied by degeneration of mitochondrial functions. Different pathways are active to counteract the processes which lead to mitochondrial dysfunction. Mitochondrial dynamics, the fission and fusion of mitochondria, is one of these quality control pathways. Mitophagy, the controlled degradation of mitochondria, is another one. Here we show that these pathways are linked. A double deletion mutant of Saccharomyces cerevisiae in which two essential components of the fission and fusion machinery, Dnm1 and Mgm1, are simultaneously ablated, contain wild-type like filamentous mitochondria, but are characterized by impaired respiration, an increased sensitivity to different stressors, increased mitochondrial protein carbonylation, and a decrease in mitophagy and replicative lifespan. These data show that a balanced mitochondrial dynamics and not a filamentous mitochondrial morphotype per se is the key for a long lifespan and demonstrate a cross-talk between two different mitochondrial quality control pathways.

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Section: Discussionmentioning

confidence: 85%

Simultaneous impairment of mitochondrial fission and fusion reduces mitophagy and shortens replicative lifespan

Bernhardt

Müller

Reichert

et al. 2015

Sci Rep

Self Cite

102

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“…In summary, CS-induced mitochondrial hyperfusion might serve as an adaptive response to increase mitochondrial ATP production to cope with CSE-induced cell damage. A hyperfused mitochondrial network, however, may render the cell more vulnerable to additional stress, as it attenuates mitochondrial quality control (14). Moreover, because elongated mitochondria are spared from removal by autophagy (16), sustained mitochondrial hyperfusion, attributable to continuous and chronic exposure to stress, might further increase susceptibility upon additional stress of the mitochondrial network.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells

Ballweg

Mutze

Königshoff

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

111

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Ballweg K, Mutze K, Königshoff M, Eickelberg O, Meiners S. Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 307: L895-L907, 2014. First published October 17, 2014 doi:10.1152/ajplung.00180.2014.-Cigarette smoke is the main risk factor for chronic obstructive pulmonary disease (COPD). Exposure of cells to cigarette smoke induces an initial adaptive cellular stress response involving increased oxidative stress and induction of inflammatory signaling pathways. Exposure of mitochondria to cellular stress alters their fusion/fission dynamics. Whereas mild stress induces a prosurvival response termed stressinduced mitochondrial hyperfusion, severe stress results in mitochondrial fragmentation and mitophagy. In the present study, we analyzed the mitochondrial response to mild and nontoxic doses of cigarette smoke extract (CSE) in alveolar epithelial cells. We characterized mitochondrial morphology, expression of mitochondrial fusion and fission genes, markers of mitochondrial proteostasis, as well as mitochondrial functions such as membrane potential and oxygen consumption. Murine lung epithelial (MLE)12 and primary mouse alveolar epithelial cells revealed pronounced mitochondrial hyperfusion upon treatment with CSE, accompanied by increased expression of the mitochondrial fusion protein mitofusin 2 and increased metabolic activity. We did not observe any alterations in mitochondrial proteostasis, i.e., induction of the mitochondrial unfolded protein response or mitophagy. Therefore, our data indicate an adaptive prosurvival response of mitochondria of alveolar epithelial cells to nontoxic concentrations of CSE. A hyperfused mitochondrial network, however, renders the cell more vulnerable to additional stress, such as sustained cigarette smoke exposure. As such, cigarette smoke-induced mitochondrial hyperfusion, although part of a beneficial adaptive stress response in the first place, may contribute to the pathogenesis of COPD. chronic obstructive pulmonary disease; emphysema; proteostasis; stress-induced mitochondrial hyperfusion CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is one of the leading causes of death worldwide. It is characterized by progressive and irreversible airflow limitation (4, 44). In the Western world, the main risk factor for development of COPD is cigarette smoke (CS) (4, 44), which is a complex mixture of thousands of injurious agents and reactive oxidants (7,33,44). Exposure of lung epithelial cells to CS initiates an adaptive cell response, such as induction of autophagy, impaired proteasome function, and proinflammatory and oxidative responses (7,33,35).Mitochondria are crucial cellular organelles for cellular energetics, signaling, and apoptosis. Differences in cellular energy demands or cellular stress rapidly alter mitochondrial behavior mainly by changing mitochondrial fusion and fission dynamics (5, 9, 26). Mitochondrial hyperfusion provides a stress-resolving mechanism for the cell, as elongated mitochondria are pr...

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“…In this mathematical model, the generation of molecular damage, spread of damage, biogenesis of cellular components, mitochondrial fission and fusion, and mitophagy, as a type of selective autophagy, are modeled and simulated. The results indicate that the analyzed pathways effectively cooperate in a regulated way to keep mitochondria functional over time 29 , 30 . While the role of mitochondrial dynamics on aging was first reported in P. anserina 31 and the impact of the generation of damage has been previously demonstrated, 32 the impact of autophagy on aging has not been investigated yet although autophagy has been studied in the context of vegetative incompatibility between strains of different genotypes and found to protect cells against death 33 - 35 …”

Section: Introductionmentioning

confidence: 96%

Identification of autophagy as a longevity-assurance mechanism in the aging modelPodospora anserina

Knuppertz

Hamann

Pampaloni³

et al. 2014

Autophagy

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The filamentous ascomycete Podospora anserina is a well-established aging model in which a variety of different pathways, including those involved in the control of respiration, ROS generation and scavenging, DNA maintenance, proteostasis, mitochondrial dynamics, and programmed cell death have previously been demonstrated to affect aging and life span. Here we address a potential role of autophagy. We provide data demonstrating high basal autophagy levels even in strains cultivated under noninduced conditions. By monitoring an N-terminal fusion of EGFP to the fungal LC3 homolog PaATG8 over the lifetime of the fungus on medium with and without nitrogen supplementation, respectively, we identified a significant increase of GFP puncta in older and in nitrogen-starved cultures suggesting an induction of autophagy during aging. This conclusion is supported by the demonstration of an age-related and autophagy-dependent degradation of a PaSOD1-GFP reporter protein. The deletion of Paatg1, which leads to the lack of the PaATG1 serine/threonine kinase active in early stages of autophagy induction, impairs ascospore germination and development and shortens life span. Under nitrogen-depleted conditions, life span of the wild type is increased almost 4-fold. In contrast, this effect is annihilated in the Paatg1 deletion strain, suggesting that the ability to induce autophagy is beneficial for this fungus. Collectively, our data identify autophagy as a longevity-assurance mechanism in P. anserina and as another surveillance pathway in the complex network of pathways affecting aging and development. These findings provide perspectives for the elucidation of the mechanisms involved in the regulation of individual pathways and their interactions.

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Quality control of mitochondria during aging: Is there a good and a bad side of mitochondrial dynamics?

Cited by 26 publications

References 78 publications

Simultaneous impairment of mitochondrial fission and fusion reduces mitophagy and shortens replicative lifespan

Simultaneous impairment of mitochondrial fission and fusion reduces mitophagy and shortens replicative lifespan

Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells

Identification of autophagy as a longevity-assurance mechanism in the aging modelPodospora anserina

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