{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T16:02:11Z","timestamp":1771603331258,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T00:00:00Z","timestamp":1731628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Translational Genomics, Maastricht of University, The Netherlands"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["ncRNA"],"abstract":"<jats:p>Primary mitochondrial disease (MD) is a group of rare genetic diseases reported to have a prevalence of 1:5000 and is currently without a cure. This group of diseases includes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), Leber\u2019s hereditary optic neuropathy (LHON), Leigh syndrome (LS), Kearns\u2013Sayre syndrome (KSS), and myoclonic epilepsy and ragged-red fiber disease (MERRF). Additionally, secondary mitochondrial dysfunction has been implicated in the most common current causes of mortality and morbidity, including cardiovascular disease (CVD) and cancer. Identifying key genetic contributors to both MD and secondary mitochondrial dysfunction may guide clinicians to assess the most effective treatment course and prognosis, as well as informing family members of any hereditary risk of disease transmission. Identifying underlying genetic causes of primary and secondary MD involves either genome sequencing (GS) or small targeted panel analysis of known disease-causing nuclear- or mitochondrial genes coding for mitochondria-related proteins. Due to advances in GS, the importance of long non-coding RNA (lncRNA) as functional contributors to the pathophysiology of MD is being unveiled. A limited number of studies have thus far reported the importance of lncRNAs in relation to MD causation and progression, and we are entering a new area of attention for clinical geneticists in specific rare malignancies. This commentary provides an overview of what is known about the role of lncRNAs as genetic and molecular contributors to disease pathophysiology and highlights an unmet need for a deeper understanding of mitochondrial dysfunction in serious human disease burdens.<\/jats:p>","DOI":"10.3390\/ncrna10060057","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T07:51:15Z","timestamp":1732002675000},"page":"57","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["LNC-ing Genetics in Mitochondrial Disease"],"prefix":"10.3390","volume":"10","author":[{"given":"Rick","family":"Kamps","sequence":"first","affiliation":[{"name":"Department of Translational Genomics, School for Mental Health and Neuroscience (MHeNS), Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4866-731X","authenticated-orcid":false,"given":"Emma Louise","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1101\/gr.132159.111","article-title":"The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression","volume":"22","author":"Derrien","year":"2012","journal-title":"Genome Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"D766","DOI":"10.1093\/nar\/gky955","article-title":"GENCODE reference annotation for the human and mouse genomes","volume":"47","author":"Frankish","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"jcs258937","DOI":"10.1242\/jcs.258937","article-title":"Expression analysis and function of mitochondrial genome-encoded microRNAs","volume":"135","author":"Kuthethur","year":"2022","journal-title":"J. Cell Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1093\/nar\/gkz073","article-title":"LncBook: A curated knowledgebase of human long non-coding RNAs (vol 47, pg D128, 2019)","volume":"47","author":"Ma","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cao, J.N. (2014). The functional role of long non-coding RNAs and epigenetics. Biol. Proced. Online, 16.","DOI":"10.1186\/1480-9222-16-11"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Azodi, M., Kamps, R., Heymans, S., and Robinson, E.L. (2020). The Missing \u201clnc\u201d between Genetics and Cardiac Disease. Non-Coding RNA, 6.","DOI":"10.3390\/ncrna6010003"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Theunissen, T.E.J., Nguyen, M., Kamps, R., Hendrickx, A.T., Sallevelt, S.C.E.H., Gottschalk, R.W.H., Calis, C.M., Stassen, A.P.M., de Koning, B., and Mulder-Den Hartog, E.N.M. (2018). Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause. Front. Genet., 9.","DOI":"10.3389\/fgene.2018.00400"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/jimd.12507","article-title":"How to proceed after \u201cnegative\u201d exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques","volume":"45","author":"Wortmann","year":"2022","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_9","first-page":"93","article-title":"Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator","volume":"592","author":"Allou","year":"2021","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.ajhg.2021.04.025","article-title":"Non-coding region variants upstream of cause severe developmental disorder through three distinct loss-of-function mechanisms","volume":"108","author":"Wright","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1161\/CIRCRESAHA.114.304028","article-title":"LIPCAR: A mitochondrial lnc in the noncoding RNA chain?","volume":"114","author":"Dorn","year":"2014","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/s41569-023-00952-5","article-title":"Long non-coding RNAs in cardiac hypertrophy and heart failure: Functions, mechanisms and clinical prospects","volume":"21","author":"Mably","year":"2024","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1002\/ejhf.3139","article-title":"Efficacy and safety of CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: Rationale and design of the HF-REVERT trial","volume":"26","author":"Bauersachs","year":"2024","journal-title":"Eur. J. Heart Fail"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9430","DOI":"10.1073\/pnas.0903086106","article-title":"Expression of a family of noncoding mitochondrial RNAs distinguishes normal from cancer cells","volume":"106","author":"Burzio","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1261\/rna.029405.111","article-title":"Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins","volume":"17","author":"Rackham","year":"2011","journal-title":"RNA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41419-019-1649-3","article-title":"Mitochondrial ncRNA targeting induces cell cycle arrest and tumor growth inhibition of MDA-MB-231 breast cancer cells through reduction of key cell cycle progression factors","volume":"10","author":"Fitzpatrick","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.7150\/jca.38880","article-title":"Targeting antisense mitochondrial noncoding RNAs induces bladder cancer cell death and inhibition of tumor growth through reduction of survival and invasion factors","volume":"11","author":"Borgna","year":"2020","journal-title":"J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.apsb.2020.10.001","article-title":"Long non-coding RNAs: From disease code to drug role","volume":"11","author":"Chen","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1161\/CIRCRESAHA.114.303915","article-title":"Circulating long noncoding RNA, LIPCAR, predicts survival in patients with heart failure","volume":"114","author":"Kumarswamy","year":"2014","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s10545-011-9292-x","article-title":"Mitochondrial medicine","volume":"34","author":"Koene","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s10545-017-0133-4","article-title":"\u201cTranscriptomics\u201d: Molecular diagnosis of inborn errors of metabolism via RNA-sequencing","volume":"41","author":"Kremer","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gusic, M., and Prokisch, H. (2020). Corrigendum: ncRNAs: New Players in Mitochondrial Health and Disease?. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.00288"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Steyaert, W., Sagath, L., Demidov, G., Yepez, V.A., Esteve-Codina, A., Gagneur, J., Ellwanger, K., Derks, R., Weiss, M., and den Ouden, A. (2024). Unravelling undiagnosed rare disease cases by HiFi long-read genome sequencing. medRxiv.","DOI":"10.1101\/2024.05.03.24305331"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.mito.2017.08.002","article-title":"Two novel lncRNAs discovered in human mitochondrial DNA using PacBio full-length transcriptome data","volume":"38","author":"Gao","year":"2018","journal-title":"Mitochondrion"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.mito.2021.06.005","article-title":"A hitchhiker\u2019s guide to mitochondrial quantification","volume":"59","author":"Hemel","year":"2021","journal-title":"Mitochondrion"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102262","DOI":"10.1016\/j.omtn.2024.102262","article-title":"Guidelines for mitochondrial RNA analysis","volume":"35","author":"Jusic","year":"2024","journal-title":"Mol. Ther. Nucl. Acids."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"C482","DOI":"10.1152\/ajpcell.00446.2021","article-title":"Manipulation of the miR-378a\/mt-ATP6 regulatory axis rescues ATP synthase in the diabetic heart and offers a novel role for lncRNA Kcnq1ot1","volume":"322","author":"Durr","year":"2022","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e45051","DOI":"10.7554\/eLife.45051","article-title":"The long non-coding RNA is a post transcriptional regulator of mitochondrial complex I catalytic activity","volume":"8","author":"Sirey","year":"2019","journal-title":"Elife"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.omtn.2020.09.040","article-title":"Nuclear-Encoded lncRNA Epigenetically Controls Metabolic Reprogramming in HCC Cells through the Mitophagy Pathway","volume":"23","author":"Zhao","year":"2021","journal-title":"Mol. Ther-Nucl. Acids."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nature17161","article-title":"Melanoma addiction to the long non-coding RNA","volume":"531","author":"Leucci","year":"2016","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/s41388-021-02051-6","article-title":"The long non-coding RNA is essential for uveal melanoma cell survival (Sept, 10.1038\/s41388-021-02006-x, 2021)","volume":"41","author":"Dewaele","year":"2022","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Orre, C., Dieu, X., Guillon, J., Gueguen, N., Ahmadpour, S.T., Dumas, J.F., Khiati, S., Reynier, P., Lenaers, G., and Coqueret, O. (2021). The Long Non-Coding RNA SAMMSON Is a Regulator of Chemosensitivity and Metabolic Orientation in MCF-7 Doxorubicin-Resistant Breast Cancer Cells. Biology, 10.","DOI":"10.3390\/biology10111156"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kobayashi, A., Takeiwa, T., Ikeda, K., and Inoue, S. (2023). Roles of Noncoding RNAs in Regulation of Mitochondrial Electron Transport Chain and Oxidative Phosphorylation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119414"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Liu, X., and Shan, G. (2021). Mitochondria Encoded Non-coding RNAs in Cell Physiology. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.713729"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sun, W.H., Lu, Y.J., Zhang, H., Zhang, J., Fang, X.Y., Wang, J.X., and Li, M.Y. (2022). Mitochondrial Non-Coding RNAs Are Potential Mediators of Mitochondrial Homeostasis. Biomolecules, 12.","DOI":"10.3390\/biom12121863"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13072-017-0149-x","article-title":"Long noncoding RNAs coordinate functions between mitochondria and the nucleus","volume":"10","author":"Dong","year":"2017","journal-title":"Epigenet. Chromatin"}],"container-title":["Non-Coding RNA"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2311-553X\/10\/6\/57\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:33:18Z","timestamp":1760113998000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2311-553X\/10\/6\/57"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,15]]},"references-count":36,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ncrna10060057"],"URL":"https:\/\/doi.org\/10.3390\/ncrna10060057","relation":{},"ISSN":["2311-553X"],"issn-type":[{"value":"2311-553X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,15]]}}}