Disruption of the MICOS complex leads to an aberrant cristae structure and an unexpected, pronounced lifespan extension in Podospora anserina
Disruption of the MICOS complex leads to an aberrant cristae structure and an unexpected, pronounced lifespan extension in Podospora anserina
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DOI：
10.1002/jcb.30278
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发表时间：
2022-03
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通讯作者：
Verena Warnsmann;Lisa-Marie Marschall;Anja C Meeßen;Maike Wolters;Lea Schürmanns;Marion Basoglu;S. Eimer;H. Osiewacz
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作者：
Verena Warnsmann;Lisa-Marie Marschall;Anja C Meeßen;Maike Wolters;Lea Schürmanns;Marion Basoglu;S. Eimer;H. Osiewacz
线粒体是一种动态的真核细胞器，参与多种必要的细胞过程，包括三磷酸腺苷（ATP）和活性氧（ROS）的产生，以及细胞凋亡和自噬的控制。线粒体功能受损会导致衰老和疾病。先前对子囊菌的研究表明，线粒体形态型和线粒体超微结构在衰老过程中发生变化。后者伴随着线粒体内膜的年龄依赖性重组，导致从板层嵴到泡状结构的变化。特别是从酵母的研究中，我们知道除了f1fo - atp合成酶和磷脂心磷脂外，Mic60-和mic10亚复合物的“线粒体接触位点和嵴组织系统”（MICOS）复合物对于正常的嵴形成至关重要。在本研究中，我们旨在了解线粒体超微结构与年龄相关变化的机制基础。我们观察到MICOS亚基在转录后水平被共同调控。这种调节部分依赖于线粒体iaaa蛋白酶PaIAP。最令人惊讶的是，我们得出了一个违反直觉的观察结果，尽管失去了板层嵴和线粒体损伤，但MICOS亚基（PaMIC12除外）的消失会导致明显的寿命延长。此外，同时消融两种MICOS亚复合物的亚基可协同延长寿命，这提供了正式的遗传证据，表明这两种亚复合物通过不同且至少部分独立的途径影响寿命。在分子水平上，我们发现mic10亚复合物成分的消弭导致有丝分裂诱导的寿命延长，而mic60亚复合物突变体的寿命延长似乎由另一途径控制。综上所述，我们的数据表明，这两个MICOS亚复合物具有不同的功能，在鹅斑孢杆菌的衰老过程中发挥着不同的作用。
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.