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Despite 5 decades of intensive research, no protein has been universally accepted as essential for mPTP opening, limiting mechanistic understanding and raising questions about the validity of mPTP-targeted strategies to mitigate cardiac ischemia\u2013reperfusion (I\/R) injury. Here, we discuss convergent findings from two independent laboratories identifying the innate immune receptor NLRX1 as an unexpected, essential requirement for mPTP activity. NLRX1 is the only NOD-like receptor (NLR) that is targeted to the mitochondrion. NLRX1 deficiency abolishes (1) calcium-induced mPTP opening, (2) cyclosporine A sensitivity of the pore, and (3) mitochondrial calcium release following cardiac I\/R. To test whether loss of mPTP function aligns with loss of NLRX1 across evolution, we performed forward and reciprocal bioinformatic (Blastp) searches and found that species reported to lack an mPTP (e.g.,\n                    <jats:italic>Artemia franciscana<\/jats:italic>\n                    and\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    ) also lack NLRX1, further supporting a mandatory role for NLRX1 in mPTP occurrence. Notably, NLRX1-deficient hearts can exhibit increased, rather than decreased, I\/R injury at specific ischemia durations. This mirrors reports that deletion of established mPTP regulators (e.g.,\n                    <jats:italic>Ppif<\/jats:italic>\n                    ) may also worsen injury under defined conditions, consistent with context-dependent, potentially protective roles for transient mPTP activity (e.g., mitochondrial calcium release, PI3K\/Akt signaling). In summary, we propose that NLRX1 is the only currently identified protein that is strictly required for mPTP opening, and that indiscriminate inhibition of the mPTP is unlikely to represent a universally effective cardioprotective strategy against I\/R injury.\n                  <\/jats:p>","DOI":"10.1007\/s00395-026-01204-6","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T16:26:00Z","timestamp":1787156760000},"page":"827-835","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NLRX1 emerges as the only observed essential regulator of the mPTP, challenging mPTP inhibition as a valid target of cardioprotection"],"prefix":"10.1007","volume":"121","author":[{"given":"Kielen R.","family":"Zuurbier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8361-2448","authenticated-orcid":false,"given":"Coert J.","family":"Zuurbier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"1204_CR1","doi-asserted-by":"publisher","first-page":"41637","DOI":"10.1074\/jbc.M110.137885","volume":"285","author":"AA Abdul-Sater","year":"2010","unstructured":"Abdul-Sater AA, Sa\u00efd-Sadier N, Lam VM, Singh B, Pettengill MA, Soares F, Tattoli I, Lipinski S, Girardin SE, Rosenstiel P, Ojcius DM (2010) Enhancement of reactive oxygen species production and chlamydial infection by the mitochondrial Nod-like family member NLRX1. 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