Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.
Membrane contact sites between virtually any known organelle have been documented and, in the last decades, their study received momentum due to their importance for fundamental activities of the cell and for the subtle comprehension of many human diseases. The lack of tools to finely image inter-organelle proximity hindered our understanding on how these subcellular communication hubs mediate and regulate cell homeostasis. We develop an improved and expanded palette of split-GFP-based contact site sensors (SPLICS) for the detection of single and multiple organelle contact sites within a scalable distance range. We demonstrate their flexibility under physiological conditions and in living organisms.
Metastatic breast cancer cells disseminate to organs with a soft
microenvironment. Whether and how local tissue mechanical properties influence
their response to treatment remains unclear. Here we found that a soft ECM
empowers redox homeostasis. Cells cultured on a soft ECM display increased
peri-mitochondrial F-actin promoted by Spire1C and Arp2/3 nucleation factors,
and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in
mitochondrial dynamics lead to increased mtROS production and activate the NRF2
antioxidant transcriptional response, including increased cystine uptake and
glutathione metabolism. This retrograde response endows cells with resistance to
oxidative stress and ROS-dependent chemotherapy drugs. This is relevant in a
mouse model of metastatic breast cancer cells dormant in the lung soft tissue,
where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented
disseminated cancer cell awakening. We propose that targeting this mitochondrial
dynamics- and redox-based mechanotransduction pathway could open avenues to
prevent metastatic relapse.
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