Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
Department of Chemistry, MIN Faculty, Universität Hamburg, Hamburg, Germany.
Nat Commun. 2024 Aug 27;15(1):7352. doi: 10.1038/s41467-024-51680-4.
The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.
线粒体通过分裂和融合实现形态的动态调控，对于细胞对刺激的反应至关重要。在稳态细胞中，两种分裂模式——中膜分裂和外周分裂——为线粒体的增殖或清除提供了决策分支。然而，在许多生物学背景下，特定线粒体形态和功能之间的关系仍然不清楚。尽管碎片化的线粒体通常与生物能量降低有关，但在几种疾病状态下，包括感染常见病原体人巨细胞病毒 (HCMV) 和转移性黑色素瘤，它们的呼吸作用反而升高，这是一个悖论。在这里，我们将超分辨率显微镜与质谱和代谢测定相结合，利用 HCMV 感染来建立维持碎片化线粒体群体呼吸作用的分子机制。我们确定 HCMV 通过与线粒体融合抑制相关的外周线粒体分裂诱导分裂。与未感染的细胞不同，外周分裂的后代进入线粒体-内质网包裹（MENCs），在感染过程中它们在那里免受降解并在能量代谢上得到稳定。MENCs 还稳定了促病毒的线粒体间接触（IMCs），这些接触在线粒体之间建立电化学连接并促进呼吸作用。证明了更广泛的相关性，我们表明转移性黑色素瘤细胞内的碎片化线粒体也形成了 MENCs。我们的发现建立了一个机制，即线粒体碎片化可以促进呼吸作用的增加，这在人类疾病的背景下具有重要意义。
