{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T21:20:48Z","timestamp":1777670448431,"version":"3.51.4"},"reference-count":65,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T00:00:00Z","timestamp":1645747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM071813"],"award-info":[{"award-number":["R01GM071813"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10 OD025230"],"award-info":[{"award-number":["S10 OD025230"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Recent studies on nuclear-encoded mitochondrial genes (N-mt genes) in Drosophila melanogaster have shown a unique pattern of expression for newly duplicated N-mt genes, with many duplicates having a testis-biased expression and playing an essential role in spermatogenesis. In this study, we investigated a newly duplicated N-mt gene\u2014i.e., Cytochrome c oxidase 4-like (COX4L)\u2014in order to understand its function and, consequently, the reason behind its retention in the D. melanogaster genome. The COX4L gene is a duplicate of the Cytochrome c oxidase 4 (COX4) gene of OXPHOS complex IV. While the parental COX4 gene has been found in all eukaryotes, including single-cell eukaryotes such as yeast, we show that COX4L is only present in the Brachycera suborder of Diptera; thus, both genes are present in all Drosophila species, but have significantly different patterns of expression: COX4 is highly expressed in all tissues, while COX4L has a testis-specific expression. To understand the function of this new gene, we first knocked down its expression in the D. melanogaster germline using two different RNAi lines driven by the bam-Gal4 driver; second, we created a knockout strain for this gene using CRISPR-Cas9 technology. Our results showed that knockdown and knockout lines of COX4L produce partial sterility and complete sterility in males, respectively, where a lack of sperm individualization was observed in both cases. Male infertility was prevented by driving COX4L-HA in the germline, but not when driving COX4-HA. In addition, ectopic expression of COX4L in the soma caused embryonic lethality, while overexpression in the germline led to a reduction in male fertility. COX4L-KO mitochondria show reduced membrane potential, providing a plausible explanation for the male sterility observed in these flies. This prominent loss-of-function phenotype, along with its testis-biased expression and its presence in the Drosophila sperm proteome, suggests that COX4L is a paralogous, specialized gene that is assembled in OXPHOS complex IV of male germline cells and\/or sperm mitochondria.<\/jats:p>","DOI":"10.3390\/genes13030424","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T10:00:40Z","timestamp":1645783240000},"page":"424","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["COX4-like, a Nuclear-Encoded Mitochondrial Gene Duplicate, Is Essential for Male Fertility in Drosophila melanogaster"],"prefix":"10.3390","volume":"13","author":[{"given":"Mohammadmehdi","family":"Eslamieh","sequence":"first","affiliation":[{"name":"Department of Biology, The University of Texas at Arlington, Arlington, TX 76019, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayda","family":"Mirsalehi","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of Texas at Arlington, Arlington, TX 76019, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dragomira N.","family":"Markova","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of Texas at Arlington, Arlington, TX 76019, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4742-7963","authenticated-orcid":false,"given":"Esther","family":"Betr\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of Texas at Arlington, Arlington, TX 76019, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.tem.2015.12.001","article-title":"Mitochondrial Dynamics and Metabolic Regulation","volume":"27","author":"Wai","year":"2016","journal-title":"Trends Endocrinol. 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