Developmental mitochondrial Complex I activity determines lifespan-猫眼课题宝

DOI：

10.1101/2023.06.21.545894

发表时间：

2023-06

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Rhoda Stefanatos;Fiona Robertson;A. Uribe;Yizhou Yu;Kevin Myers;Beatriz Castejón-Vega;T. Kataura;L. Martins;V. Korolchuk;Oliver D. K. Maddocks;A. Sanz

线粒体功能异常与越来越多的人类疾病状态有关。对线粒体功能改变的活体模型的观察表明，对线粒体功能障碍的适应可能是疾病病理的基础。我们假设，当线粒体功能障碍表现出来时，这些适应不良的严重程度可能由系统的可塑性决定。为了研究这一点，我们使用了线粒体复合体I(CI)功能障碍的诱导性果蝇模型，在果蝇生命周期的两个阶段--从早期发育和成虫羽化--降低线粒体功能。在这里，我们表明，在生命早期(发育)，线粒体功能障碍会导致成年后存活率和抗应激能力的严重下降，而线粒体功能从成年期开始受到干扰的果蝇，尽管CI活性降低了75%，但仍然长寿并耐受压力。在排除了发育缺陷的原因后，我们继续对这两种线粒体受损的果蝇进行了分子特征分析，分别是短期和长期的。我们发现，我们的短命果蝇有独特的转录和代谢反应，这些反应在CI功能障碍的谨慎模型中显著重叠。我们的数据表明，早期线粒体功能障碍通过CI耗竭引起的适应性反应严重降低了存活率，而成年期的CI耗竭不足以降低存活率和应激抵抗力。

Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that adaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of these maladaptations could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to an 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic and metabolomic responses which overlap significantly in discreet models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits an adaptive response which severely reduces survival, while CI depletion from adulthood is not sufficient to reduce survival and stress resistance.

Developmental mitochondrial Complex I activity determines lifespan

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