{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:57:01Z","timestamp":1790575021744,"version":"4.1.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Mitochondrial dysfunction is a hallmark of Parkinson\u2019s disease (PD), but how impaired mitochondrial homeostasis drives the selective death of dopaminergic neurons is still poorly understood. At the center of this problem lies the mitochondrial protein import machinery\u2014the TOM and TIM23 translocases\u2014which doubles as a stress-sensing hub that coordinates two distinct quality control pathways. When import is compromised, the kinase PINK1 accumulates on the mitochondrial surface, recruits Parkin to ubiquitinate outer membrane proteins, and triggers mitophagy. Meanwhile, the stress sensor DELE1 is cleaved and released to the cytosol, where it activates the HRI kinase to phosphorylate eIF2\u03b1 and engage the integrated stress response (ISR). These two pathways are not independent. Recent work shows they engage in antagonistic crosstalk: the DELE1\u2013HRI\u2013ISR axis suppresses PINK1\/Parkin-dependent mitophagy by preserving mitochondrial import efficiency, acting as a molecular brake on organelle clearance. The balance between these pathways is governed by the SIFI E3 ubiquitin ligase complex, which targets both DELE1 and HRI for degradation. Disruption of SIFI causes progressive neurodegeneration in humans. Here we synthesize the structural, biochemical, and genetic evidence that defines the TOM\/TIM\u2013PINK1\/Parkin\u2013DELE1\/HRI signaling axis, examine how its dysregulation contributes to dopaminergic neuron vulnerability, and evaluate therapeutic strategies targeting mitochondrial import stress in PD.<\/jats:p>","DOI":"10.3389\/fcell.2026.1935788","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:43:34Z","timestamp":1790574214000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial protein import stress in Parkinson\u2019s disease: the TOM\/TIM\u2013PINK1\/Parkin\u2013DELE1\/HRI axis linking mitochondrial proteostasis to neuronal death"],"prefix":"10.3389","volume":"14","author":[{"given":"Bo","family":"Pang","sequence":"first","affiliation":[{"name":"College of Pharmacy, Jining Medical University","place":["Rizhao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jining Medical University","place":["Rizhao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jining Medical University","place":["Rizhao, Shandong, China"]},{"name":"Institute of Pharmacy, Shandong University of Traditional Chinese Medicine","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Ding","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jining Medical University","place":["Rizhao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"112454","DOI":"10.1016\/j.celrep.2023.112454","article-title":"TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria","volume":"42","author":"Akabane","year":"2023","journal-title":"Cell Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/s41586-019-1680-7","article-title":"Structure of the mitochondrial import gate reveals distinct preprotein paths","volume":"575","author":"Araiso","year":"2019","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1083\/jcb.201708044","article-title":"Tom70 enhances mitochondrial preprotein import efficiency by binding to internal targeting sequences","volume":"217","author":"Backes","year":"2018","journal-title":"J. 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