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The physical-functional coupling of the endoplasmic reticulum (ER) with mitochondria allows for the direct transfer of Ca<jats:sup>2+<\/jats:sup> between organelles and is an important avenue for rapidly increasing mitochondrial metabolic activity. As such, increasing ER\u2212mitochondrial coupling can boost the generation of ATP that is needed to restore homeostasis in the face of cellular stress. The mitochondrial unfolded protein response (mtUPR) is activated by the accumulation of unfolded proteins in mitochondria. Retrograde signaling from mitochondria to the nucleus promotes mtUPR transcriptional responses aimed at restoring protein homeostasis. It is currently unknown whether the changes in mitochondrial\u2212ER coupling also play a role during mtUPR stress. We hypothesized that mitochondrial stress favors an expansion of functional contacts between mitochondria and ER, thereby increasing mitochondrial metabolism as part of a protective response. Hela cells were treated with doxycycline, an antibiotic that inhibits the translation of mitochondrial-encoded proteins to create protein disequilibrium. Treatment with doxycycline decreased the abundance of mitochondrial encoded proteins while increasing expression of CHOP, C\/EBP\u03b2, ClpP, and mtHsp60, markers of the mtUPR. There was no change in either mitophagic activity or cell viability. Furthermore, ER UPR was not activated, suggesting focused activation of the mtUPR. Within 2\u2009h of doxycycline treatment, there was a significant increase in physical contacts between mitochondria and ER that was distributed throughout the cell, along with an increase in the kinetics of mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake. This was followed by the rise in the rate of oxygen consumption at 4\u2009h, indicating a boost in mitochondrial metabolic activity. In conclusion, an early phase of the response to doxycycline-induced mitochondrial stress is an increase in mitochondrial\u2212ER coupling that potentiates mitochondrial metabolic activity as a means to support subsequent steps in the mtUPR pathway and sustain cellular adaptation.<\/jats:p>","DOI":"10.1038\/s41419-021-03945-9","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T13:03:17Z","timestamp":1624885397000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Endoplasmic reticulum\u2212mitochondria coupling increases during doxycycline-induced mitochondrial stress in HeLa cells"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1055-099X","authenticated-orcid":false,"given":"Camila","family":"Lopez-Crisosto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5227-4482","authenticated-orcid":false,"given":"Alexis","family":"D\u00edaz-Vegas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9320-1703","authenticated-orcid":false,"given":"Pablo F.","family":"Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9037-6703","authenticated-orcid":false,"given":"Beverly A.","family":"Rothermel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8873-8699","authenticated-orcid":false,"given":"Roberto","family":"Bravo-Sagua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4258-1483","authenticated-orcid":false,"given":"Sergio","family":"Lavandero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,28]]},"reference":[{"key":"3945_CR1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.biocel.2014.01.019","volume":"50","author":"R Bravo-Sagua","year":"2014","unstructured":"Bravo-Sagua R, Torrealba N, Paredes F, Morales PE, Pennanen C, L\u00f3pez-Crisosto C, et al. 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