bims-cytox1 2022-12-11 papers

Issue of 2022‒12‒11
three papers selected by
Gavin McStay
Liverpool John Moores University

Open Biol. 2022 Dec;12(12): 220274

Mitochondrial biology and dysfunction in secondary mitochondrial disease.

Megan J Baker, Jordan J Crameri, David R Thorburn, Ann E Frazier, Diana Stojanovski.

Mitochondrial diseases are a broad, genetically heterogeneous class of metabolic disorders characterized by deficits in oxidative phosphorylation (OXPHOS). Primary mitochondrial disease (PMD) defines pathologies resulting from mutation of mitochondrial DNA (mtDNA) or nuclear genes affecting either mtDNA expression or the biogenesis and function of the respiratory chain. Secondary mitochondrial disease (SMD) arises due to mutation of nuclear-encoded genes independent of, or indirectly influencing OXPHOS assembly and operation. Despite instances of novel SMD increasing year-on-year, PMD is much more widely discussed in the literature. Indeed, since the implementation of next generation sequencing (NGS) techniques in 2010, many novel mitochondrial disease genes have been identified, approximately half of which are linked to SMD. This review will consolidate existing knowledge of SMDs and outline discrete categories within which to better understand the diversity of SMD phenotypes. By providing context to the biochemical and molecular pathways perturbed in SMD, we hope to further demonstrate the intricacies of SMD pathologies outside of their indirect contribution to mitochondrial energy generation.

Keywords: mitochondria; mitochondrial protein import; mitochondrial quality control; secondary mitochondrial disease

DOI: https://doi.org/10.1098/rsob.220274

Mol Med Rep. 2023 Jan;pii: 19. [Epub ahead of print]27(1):

Function of mitochondrial cytochrome c oxidase is enhanced in human lens epithelial cells at high temperatures.

Shun Takeda, Naoki Yamamoto, Noriaki Nagai, Noriko Hiramatsu, Saori Deguchi, Natsuko Hatsusaka, Eri Kubo, Hiroshi Sasaki.

Enhancement of density via human lens epithelium (HLE) cell proliferation is the underlying cause of nuclear cataracts. Moreover, our previous epidemiological study demonstrated that the risk of nuclear cataract development is significantly higher under elevated environmental temperatures compared with under lower temperatures. The present study investigated the relationship between temperature and cell proliferation in terms of mitochondrial function, which is a nuclear cataract‑inducing risk factor, using two different HLE cell lines, SRA01/04 and immortalized human lens epithelial cells NY2 (iHLEC‑NY2). Cell proliferation was significantly enhanced under the high‑temperature condition (37.5˚C) in both cell lines. The cell growth levels of SRA01/04 and iHLEC‑NY2 cells cultured at 37.5˚C were 1.20‑ and 1.16‑fold those in the low‑temperature cultures (35.0˚C), respectively. Moreover, the levels of cytochrome c oxidase mRNA (mitochondrial genome, cytochrome c oxidase‑1‑3) and its activity in SRA01/04 and iHLEC‑NY2 cells cultured at 37.5˚C were higher compared with those in cells cultured at 35.0˚C. In addition, adenosine‑5'‑triphosphate (ATP) levels in SRA01/04 and iHLEC‑NY2 cells were also significantly higher at 37.5˚C compared with those at 35.0˚C. By contrast, no significant differences in Na+/K+‑ATPase or Ca2+‑ATPase activities were observed between HLE cells cultured at 35.0 and 37.5˚C. These results suggested that expression of the mitochondrial genome was enhanced in high‑temperature culture, resulting in a sufficient ATP content and cell proliferation for lens opacity. Therefore, elevated environmental temperatures may increase the risk of nuclear cataracts caused by HLE cell proliferation via mitochondrial activation.

Keywords: ATP; cell proliferation; cytochrome c oxidase; high‑temperature culture; human; lens epithelium cell

DOI: https://doi.org/10.3892/mmr.2022.12906

EXCLI J. 2022 ;21 1306-1330

Mitochondrial mutations in protein coding genes of respiratory chain including complexes IV, V, and mt-tRNA genes are associated risk factors for congenital heart disease.

Mohammad Mehdi Heidari, Mehri Khatami, Akram Kamalipour, Mustafa Kalantari, Mahsa Movahed, Mohammad Hayet Emmamy, Mehdi Hadadzadeh, José Bragança, Mohsen Namnabat, Bahareh Mazrouei.

Most studies aiming at unraveling the molecular events associated with cardiac congenital heart disease (CHD) have focused on the effect of mutations occurring in the nuclear genome. In recent years, a significant role has been attributed to mitochondria for correct heart development and maturation of cardiomyocytes. Moreover, numerous heart defects have been associated with nucleotide variations occurring in the mitochondrial genome, affecting mitochondrial functions and cardiac energy metabolism, including genes encoding for subunits of respiratory chain complexes. Therefore, mutations in the mitochondrial genome may be a major cause of heart disease, including CHD, and their identification and characterization can shed light on pathological mechanisms occurring during heart development. Here, we have analyzed mitochondrial genetic variants in previously reported mutational genome hotspots and the flanking regions of mt-ND1, mt-ND2, mt-COXI, mt-COXII, mt-ATPase8, mt-ATPase6, mt-COXIII, and mt-tRNAs (Ile, Gln, Met, Trp, Ala, Asn, Cys, Tyr, Ser, Asp, and Lys) encoding genes by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) in 200 patients with CHD, undergoing cardiac surgery. A total of 23 mitochondrial variations (5 missense mutations, 8 synonymous variations, and 10 nucleotide changes in tRNA encoding genes) were identified and included 16 novel variants. Additionally, we showed that intracellular ATP was significantly reduced (P=0.002) in CHD patients compared with healthy controls, suggesting that the mutations have an impact on mitochondrial energy production. Functional and structural alterations caused by the mitochondrial nucleotide variations in the gene products were studied in-silico and predicted to convey a predisposing risk factor for CHD. Further studies are necessary to better understand the mechanisms by which the alterations identified in the present study contribute to the development of CHD in patients.

Keywords: congenital heart disease; in-silico analysis; mitochondrial genome; mt-tRNA; mutation

DOI: https://doi.org/10.17179/excli2022-5298