Rizzollo Francesca, Agostinis Patrizia
Cell Death Research and Therapy Laboratory, Center for Cancer Biology, VIB, Leuven, Belgium.
Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Contact (Thousand Oaks). 2025 Mar 18;8:25152564251329250. doi: 10.1177/25152564251329250. eCollection 2025 Jan-Dec.
Mitochondria and lysosomes regulate a multitude of biological processes that are essential for the maintenance of nutrient and metabolic homeostasis and overall cell viability. Recent evidence reveals that these pivotal organelles, similarly to others previously studied, communicate through specialized membrane contact sites (MCSs), hereafter referred to as mitochondria-lysosome contacts (or MLCs), which promote their dynamic interaction without involving membrane fusion. Signal integration through MLCs is implicated in key processes, including mitochondrial fission and dynamics, and the exchange of calcium, cholesterol, and amino acids. Impairments in the formation and function of MLCs are increasingly associated with age-related diseases, specifically neurodegenerative disorders and lysosomal storage diseases. However, MLCs may play roles in other pathological contexts where lysosomes and mitochondria are crucial. In this review, we introduce the methodologies used to study MLCs and discuss known molecular players and key factors involved in their regulation in mammalian cells. We also argue other potential regulatory mechanisms depending on the acidic lysosomal pH and their impact on MLC's function. Finally, we explore the emerging implications of dysfunctional mitochondria-lysosome interactions in disease, highlighting their potential as therapeutic targets in cancer.
线粒体和溶酶体调节着众多对维持营养和代谢稳态以及整体细胞活力至关重要的生物过程。最近的证据表明，这些关键细胞器与之前研究的其他细胞器类似，通过特殊的膜接触位点（MCSs）进行通讯，以下简称为线粒体 - 溶酶体接触（或 MLCs），这种接触促进它们之间的动态相互作用而不涉及膜融合。通过 MLCs 进行的信号整合参与关键过程，包括线粒体裂变和动态变化，以及钙、胆固醇和氨基酸的交换。MLCs 的形成和功能受损越来越多地与年龄相关疾病有关，特别是神经退行性疾病和溶酶体贮积病。然而，MLCs 可能在溶酶体和线粒体至关重要的其他病理环境中发挥作用。在这篇综述中，我们介绍了用于研究 MLCs 的方法，并讨论了哺乳动物细胞中已知的分子参与者和参与其调节的关键因素。我们还探讨了依赖酸性溶酶体 pH 的其他潜在调节机制及其对 MLC 功能的影响。最后，我们探讨了功能失调的线粒体 - 溶酶体相互作用在疾病中的新影响，强调了它们作为癌症治疗靶点的潜力。
