{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWithin healthy mitochondria the intramembrane‐cleaving protease PARL plays a central role in quality control by processing key regulators of mitochondrial turnover. In particular, PARL cleaves the serine/threonine kinase PINK1 within its transmembrane segment to generate a ΔN‐PINK1 fragment that underlies proper mitochondrial homeostasis and limits excessive mitophagy. Disruption of this cleavage leads to accumulation of full‐length PINK1 and altered mitochondrial morphology reminiscent of Parkinson’s disease models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPARL also modulates mitochondrial stress responses and apoptotic signaling by processing substrates that determine cell fate. It cleaves the pro‐apoptotic protein Smac to generate an N‐terminal IAP‐binding motif necessary for caspase activation and, in response to loss of mitochondrial membrane potential, conditionally cleaves PGAM5 – a phosphatase that can either promote cell survival or death. In addition, regulated cleavage events—such as a distinctive γ‐cleavage of PARL itself that alters its stability and catalytic competence—further illustrate its dynamic role in channeling mitochondrial responses between survival and apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these proteolytic events, PARL influences mitochondrial membrane organization and metabolic integrity. By cleaving the lipid transfer protein STARD7, PARL governs phosphatidylcholine distribution essential for cristae morphogenesis and respiratory function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " A wealth of genetic and biochemical studies further underscores its broad impact on human health. Variants and promoter polymorphisms in PARL have been linked to a spectrum of disorders—including Leber hereditary optic neuropathy"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", Parkinson’s disease"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}, {"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", metabolic disturbances and hyperinsulinaemia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", and primary angle closure glaucoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", as well as associations with altered mitochondrial content"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "and even leprosy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " Notably, while some studies have implicated PARL variants in these disease contexts, others (for example in schizophrenia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "have not established strong links—emphasizing that PARL’s impact may depend on tissue context and stress conditions. Additional evidence from investigations into its phosphorylation by PDK2"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "and the generation of nuclear‐targeted cleavage products"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "further supports a model in which PARL integrates mitochondrial metabolism, membrane remodeling, and apoptotic signaling into a coordinated cellular response.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Emma Deas, Helene Plun-Favreau, Sonia Gandhi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PINK1 cleavage at position A103 by the mitochondrial protease PARL."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddq526"}], "href": "https://doi.org/10.1093/hmg/ddq526"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21138942"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21138942"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Guang Shi, Jeffrey R Lee, David A Grimes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr077"}], "href": "https://doi.org/10.1093/hmg/ddr077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21355049"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21355049"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Cathrin Meissner, Holger Lorenz, Andreas Weihofen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2011.07253.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2011.07253.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21426348"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21426348"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Cathrin Meissner, Holger Lorenz, Beate Hehn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15548627.2015.1063763"}], "href": "https://doi.org/10.1080/15548627.2015.1063763"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26101826"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26101826"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Guang Shi, G Angus McQuibban "}, {"type": "b", "children": [{"type": "t", "text": "The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2017.01.029"}], "href": "https://doi.org/10.1016/j.celrep.2017.01.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28178523"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28178523"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "D V Jeyaraju, H M McBride, R B Hill, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural and mechanistic basis of Parl activity and regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cdd.2011.22"}], "href": "https://doi.org/10.1038/cdd.2011.22"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21415861"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21415861"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Shiori Sekine, Yusuke Kanamaru, Masato Koike, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.357509"}], "href": "https://doi.org/10.1074/jbc.M112.357509"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22915595"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22915595"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Shotaro Saita, Hendrik Nolte, Kai Uwe Fiedler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb3488"}], "href": "https://doi.org/10.1038/ncb3488"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28288130"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28288130"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Verena Siebert, Mara Silber, Elena Heuten, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2022.102321"}], "href": "https://doi.org/10.1016/j.jbc.2022.102321"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35921890"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35921890"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Shotaro Saita, Takashi Tatsuta, Philipp A Lampe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.201797909"}], "href": "https://doi.org/10.15252/embj.201797909"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29301859"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29301859"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Attila Sík, Brent J Passer, Eugene V Koonin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pbeta, a nuclear-targeted peptide."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M313756200"}], "href": "https://doi.org/10.1074/jbc.M313756200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14732705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14732705"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Rochmy Istikharah, Aung Win Tun, Supannee Kaewsutthi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of the variants in PARL, the nuclear modifier gene, responsible for the expression of LHON patients in Thailand."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Eye Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.exer.2013.08.007"}], "href": "https://doi.org/10.1016/j.exer.2013.08.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23973714"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23973714"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "D V Jeyaraju, G Cisbani, O M De Brito, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hax1 lacks BH modules and is peripherally associated to heavy membranes: implications for Omi/HtrA2 and PARL activity in the regulation of mitochondrial stress and apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cdd.2009.110"}], "href": "https://doi.org/10.1038/cdd.2009.110"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19680265"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19680265"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Richard Wüst, Brigitte Maurer, Kathrin Hauser, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation analyses and association studies to assess the role of the presenilin-associated rhomboid-like gene in Parkinson's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Aging (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neurobiolaging.2015.11.025"}], "href": "https://doi.org/10.1016/j.neurobiolaging.2015.11.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26778534"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26778534"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Yasuhiro Kawamoto, Takashi Ayaki, Makoto Urushitani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Accumulation of HAX-1 and PARL in brainstem- and cortical-type Lewy bodies in Parkinson's disease and dementia with Lewy bodies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jns.2020.116928"}], "href": "https://doi.org/10.1016/j.jns.2020.116928"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32470650"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32470650"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "K A Fawcett, N J Wareham, J Luan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PARL Leu262Val is not associated with fasting insulin levels in UK populations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-006-0443-9"}], "href": "https://doi.org/10.1007/s00125-006-0443-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17019603"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17019603"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Brenda L Powell, Steven Wiltshire, Gillian Arscott, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of PARL rs3732581 genetic variant with insulin levels, metabolic syndrome and coronary artery disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-008-0552-2"}], "href": "https://doi.org/10.1007/s00439-008-0552-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18758826"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18758826"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Christiane Wolf, Eugen Gramer, Bertram Müller-Myhsok, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evaluation of nine candidate genes in patients with normal tension glaucoma: a case control study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2350-10-91"}], "href": "https://doi.org/10.1186/1471-2350-10-91"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19754948"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19754948"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Fang Yao Tang, Li Ma, Pancy O S Tam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic Association of the PARL-ABCC5-HTR3D-HTR3C Locus With Primary Angle-Closure Glaucoma in Chinese."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.17-22304"}], "href": "https://doi.org/10.1167/iovs.17-22304"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28813580"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28813580"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Nopasak Phasukkijwatana, Bussaraporn Kunhapan, Jim Stankovich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-010-0821-8"}], "href": "https://doi.org/10.1007/s00439-010-0821-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20407791"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20407791"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "A-Mei Zhang, Xiaoyun Jia, Qingjiong Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "No association between the SNPs (rs3749446 and rs1402000) in the PARL gene and LHON in Chinese patients with m.11778G>A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-010-0875-7"}], "href": "https://doi.org/10.1007/s00439-010-0875-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20711738"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20711738"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Dong Wang, Deng-Feng Zhang, Jia-Qi Feng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep37086"}], "href": "https://doi.org/10.1038/srep37086"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27876828"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27876828"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Xiao Li, Wen Zhang, Chen Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common variants of the PINK1 and PARL genes do not confer genetic susceptibility to schizophrenia in Han Chinese."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Genomics (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00438-014-0942-1"}], "href": "https://doi.org/10.1007/s00438-014-0942-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25354644"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25354644"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Laine Lysyk, Raelynn Brassard, Nicolas Touret, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PARL Protease: A Glimpse at Intramembrane Proteolysis in the Inner Mitochondrial Membrane."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2020.04.006"}], "href": "https://doi.org/10.1016/j.jmb.2020.04.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32320686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32320686"}]}]}]}