Disruption of the MICOS complex leads to an aberrant cristae structure and an unexpected, pronounced lifespan extension in Podospora anserina

Abstract

Mitochondria are dynamic eukaryotic organelles involved in a variety of essential cellular processes including the generation of adenosine triphosphate (ATP) and reactive oxygen species (ROS) as well as in the control of apoptosis and autophagy. Impairments of mitochondrial functions lead to aging and disease. Previous works with the ascomycete Podospora anserina demonstrated that mitochondrial morphotype as well as mitochondrial ultrastructure change during aging. The latter goes along with an age-dependent reorganization of the inner mitochondrial membrane leading to a change from lamellar cristae to vesicular structures. Especially from studies with yeast it is known that beside the F1Fo-ATP-synthase and the phospholipid cardiolipin also the ‘mitochondrial contact site and cristae organizing system’ (MICOS) complex, existing of the Mic60- and Mic10-subcomplex, is essential for proper cristae formation. In the present study, we aimed to understand the mechanistic basis of age-related changes of the mitochondrial ultrastructure. We observed that MICOS subunits are co-regulated at the posttranscriptional level. This regulation partially depends on the mitochondrial iAAA-protease PaIAP. Most surprisingly, we made the counterintuitive observation that, despite the loss of lamellar cristae and of mitochondrial impairments, the ablation of MICOS subunits (except of PaMIC12) leads to a pronounced lifespan extension. Moreover, simultaneous ablation of subunits of both MICOS subcomplexes synergistically increases lifespan, providing formal genetic evidence that both subcomplexes affect lifespan by different and at least partially independent pathways. At the molecular level we found that ablation of Mic10-subcomplex components leads to a mitohormesis-induced lifespan extension, while lifespan extension of Mic60-subcomplex mutants seems to be controlled by another pathway. Overall, our data demonstrate that both MICOS subcomplexes have different functions and play distinct roles in the aging process of P. anserina.

Lifespan Extension of Podospora anserina Mic60-Subcomplex Mutants Depends on Cardiolipin Remodeling

“…In contrast to ∆PaTaz1, the ∆PaMic26/ ∆PaTaz1 double mutant still had an extended lifespan (Figure 3E,F), despite the lack of longchained CL species. Based on our previously described data, we concluded that longevity of the Mic10-subcomplex mutant ∆PaMic26 is the result of ROS-dependent mitohormesis [21] and does not depend on phospholipid metabolism. This conclusion is supported by the finding that loss of long-chained CL species in the mutant background only partially abrogates lifespan extension.…”

“…We found that loss of each of the two MICOS subcomplexes leads to unexpected longevity. While loss of Mic10-subcomplex results in mitohormesis-induced lifespan extension, the underlying mechanism leading to longevity in Mic60-subcomplex mutants appears to be caused by a different mechanism which may be linked to phospholipid metabolism [21]. This possibility is supported by the demonstration of the interaction between human MIC60 and components of the cardiolipin synthesis pathway, including phosphatidylglycerophosphate synthase (PGS1) and cardiolipin synthase (CRD1) [22].…”

“…Ablation of the assembly factor PaATPE leads to the loss of lamellar cristae and a mitophagy-dependent decreased lifespan [19,20]. However, the impact of the 'mitochondrial contact site and cristae organizing system' (MICOS) complex at the basis of cristae was only recently studied in detail [21]. We identified five homologs of the six well-known yeast MICOS subunits in P. anserina, also organized in two subcomplexes (Mic60-subcomplex: PaMIC60 and PaMIC19 as well as Mic10-subcomplex: PaMIC10, PaMIC26, and PaMIC12).…”

“…In this study, a counterintuitive lifespan extension was found in mutants in which individual components were ablated. Moreover, it was shown that longevity of Mic10-subcomplex mutants results from mitohormesis, the beneficial effect of mild oxidative stress [21]. Until now, the underlying mechanism of longevity in deletion mutants of the Mic60-subcomplex has not been identified.…”

The development of intracytoplasmic membranes in alphaproteobacteria involves the conserved mitochondrial crista-developing protein Mic60

“…ICMs are often continuous with, but sometimes detached from 46 , the cytoplasmic membrane (CM) 47 , just as cristae are continuous with the mitochondrial inner membrane. In S. cerevisiae mitochondria, the disruption of Mic60 leads to functional defects such as decreased growth rate under respiratory conditions (i.e., non-fermentable media) and increased production of oxygen radicals 48,49 . If Mic60 is involved in the development of photosynthetic ICMs, then its disruption should lead to growth defects in the absence of oxygen and the presence of light (i.e., photosynthetic conditions).…”