Impact of Mitochondrial Dynamics on Organismic Aging

Mitochondria, the cellular powerhouses, are mandatory to keep eukaryotic cells alive. The function of these organelles has to be regulated carefully, as they also have an important impact on the regulation of cell death programs and aging. In the past few years, it became clear that the dynamic morphology changes of mitochondria by division and fusion events play a crucial role in controlling most of these mitochondrial activities. This article examines established and putative mechanisms of how the regulation of mitochondrial dynamics influences various parameters related to aging.

fusion of juxtaposed mitochondria [20,21,22,23,24]. The exact role of the outer membrane protein Ugo1p in the fusion process has not been clearly elucidated so far. Mgm1p belongs to the class of large GTPases and has been shown to be needed for inner membrane fusion and remodeling of the cristae membranes [22,25]. The human orthologue of Mgm1, OPA-1, is known to have different splice variants that can be proteolytically processed at different sites to generate different isoforms [26,27,28,29,30,31]. Importantly, OPA-1 deficiency and mutation, respectively, are associated with a number of diseases (e.g., ADOA [autosomal dominant optic atrophy], ataxia, deafness, multiple sclerosis-like disorders) [32,33,34,35].
Mitochondrial morphology transitions have been recently shown to affect the aging of fungal model systems such as yeast and the filamentous ascomycete Podospora anserina, which has been a convenient model organism for the study of aging for more than 50 years[36,37,38].
The P. anserina mutant PaDnm1::ble, which is impaired in mitochondrial fission due to the deletion of the fission gene PaDnm1, has been characterized in recent studies [39,40]. Interestingly, in contrast to most other P. anserina longevity mutants, PaDnm1::ble does not display phenotypic defects (e.g., slow growth rate, reduced fertility, sterility). Therefore, the healthy period of the lifetime, the health span, is extended in PaDnm1::ble. In PaDnm1::ble, the normally short filamentous mitochondria appear to be highly elongated and in some cases interconnected [39]. On standard complex growth medium, PaDnm1::ble isolates benefit from a highly increased mean lifespan (244 vs. 22 days wild-type). Factors proposed to be responsible for the beneficial effect on aging are (1) a stabilized mitochondrial genome, (2) delayed fragmentation of mitochondria, (3) decreased ROS generation, and (4) [45,46], and mammalian cell lines [47,48,49,50] in which the gene that encodes the corresponding PaDNM1 orthologue has been deleted or down-regulated. Collectively, the studies show that PaDnm1::ble not only displays an extended life span, but also a prolonged health span, underlining that P. anserina is a suitable model organism to study molecular pathways leading to healthy aging.
In addition to apoptosis regulation, the control of mitochondrial dynamics has recently been identified to be important for processes that might also play vital roles for aging, autophagy of dysfunctional mitochondria (mitophagy), and resistance to ROS, respectively. Mitophagy is regarded as a pathway to recycle dysfunctional or damaged mitochondria [51]. Therefore, mitophagy plays an important role for the quality control of mitochondria. Recently, mitochondria were found to divide asymmetrically in a Drp1dependent manner [52]. One mitochondrion retained its normal membrane potential and was able to fuse with other mitochondria, whereas the other had a lowered ∆Ψ M and decreased levels of the fusion protein OPA-1 [52]. This way, the damaged mitochondrion was removed from the mitochondrial population, increasing the chance for its degradation by the autophagosome. At present, it is unclear whether this intriguing mechanism is decreased during aging and if this could also account for increased levels of dysfunctional mitochondria in old cells.
The C. elegans homologue of OPA-1, EAT-3, was identified as an essential factor for resistance against ROS [53]. If in loss-of-function mutants of eat3, the sod2 gene, encoding a mitochondrial superoxide dismutase, is down-regulated, phenotypic defects like decreased brood size are enhanced. Moreover, the eat3 mutants are also much more sensitive to the addition of a metabolic generator of superoxide anions [53]. In a mammalian cell line, it was shown that transient treatment with the ROS H 2 O 2 impairs mitochondrial dynamics and that in response to this stress, an up-regulation of various fusion and fission genes at the transcript level was found [54]. These intriguing results connect the regulation of mitochondrial morphology to the defense against oxidative stress, which might constitute a new link in the complex network that regulates aging at the cellular level.
The identification and characterization of novel cellular pathways that might bear the potential to increase the healthy period of life is one of the desired aims of experimental aging research. Mitochondrial dynamics regulation has emerged as a candidate for achieving this goal, at least in two fungal model systems, S. cerevisiae and P. anserina. It will certainly be interesting to see whether or not these molecular pathways also play similar roles in higher biological systems.