Mitochondrial Quality Control: Impact on Aging and Life Span - A Mini-Review

Osiewacz, Heinz D.; Bernhardt, Dominik

doi:10.1159/000348662

Cited by 32 publications

(37 citation statements)

References 37 publications

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“…In the past, we have demonstrated a number of different pathways to be part of such a network to affect aging and life span control in P. anserina (reviewed in refs. 8, 69, and 70). Until now, we had no experimental evidence for such an impact of autophagy.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

Knuppertz

Hamann

Pampaloni³

et al. 2014

Autophagy

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“…CLPP plays a role in the mitochondrial unfolded protein response pathway (mtUPR) by multimerizing with the CLPX chaperone within the mitochondrial matrix, thereby forming a proteasome-like cylinder that is capable of hydrolyzing mitochondrial proteins into small peptides. It is therefore expected to react upon protein conformational stress in mitochondria by inducing mitochondrial stress signaling pathways (17, 18). Molecular characterization of Clpp null mice has demonstrated that the absence of Clpp transcripts leads to significant increases in mtDNA copy number in several tissues (testis, ovary, heart, and brain) (15).…”

Section: Discussionmentioning

confidence: 99%

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

Theunissen

Szklarczyk

Gerards³

et al. 2016

Front. Neurol.

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In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient’s brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounced.

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“…This observation supports an epistatic interaction between mitochondrial inner membrane stress and cytosolic protein homeostasis in the control of replicative lifespan. A role of mitochondria in aging and lifespan control is well established [91, 92]. It has been extensively documented that adaptive mitochondria-to-nucleus signaling via the retrograde-response pathway increases cell's lifespan (for review, see [93]).…”

Section: Ant Mutations Induce Degenerative Cell Deathmentioning

confidence: 99%

Adenine Nucleotide Translocase, Mitochondrial Stress, and Degenerative Cell Death

Liu

Chen

2013

Oxidative Medicine and Cellular Longevity

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Mitochondria are intracellular organelles involved in ATP synthesis, apoptosis, calcium signaling, metabolism, and the synthesis of critical metabolic cofactors. Mitochondrial dysfunction is associated with age-related degenerative diseases. How mitochondrial dysfunction causes cell degeneration is not well understood. Recent studies have shown that mutations in the adenine nucleotide translocase (Ant) cause aging-dependent degenerative cell death (DCD) in yeast, which is sequentially manifested by inner membrane stress, mitochondrial DNA (mtDNA) loss, and progressive loss of cell viability. Ant is an abundant protein primarily involved in ADP/ATP exchange across the mitochondrial inner membrane. It also mediates basal proton leak and regulates the mitochondrial permeability transition pore. Missense mutations in the human Ant1 cause several degenerative diseases which are commonly manifested by fractional mtDNA deletions. Multiple models have been proposed to explain the Ant1-induced pathogenesis. Studies from yeast have suggested that in addition to altered nucleotide transport properties, the mutant proteins cause a global stress on the inner membrane. The mutant proteins likely interfere with general mitochondrial biogenesis in a dominant-negative manner, which secondarily destabilizes mtDNA. More recent work revealed that the Ant-induced DCD is suppressed by reduced cytosolic protein synthesis. This finding suggests a proteostatic crosstalk between mitochondria and the cytosol, which may play an important role for cell survival during aging.

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Mitochondrial Quality Control: Impact on Aging and Life Span - A Mini-Review

Cited by 32 publications

References 37 publications

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

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

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

Adenine Nucleotide Translocase, Mitochondrial Stress, and Degenerative Cell Death

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