bims-mitper 2022-10-30 papers

Issue of 2022‒10‒30
five papers selected by
Bradley Irizarry
Thomas Jefferson University

Genes (Basel). 2022 Oct 03. pii: 1789. [Epub ahead of print]13(10):

Is Mitochondria DNA Variation a Biomarker for AD?

Alzheimer's Disease (AD) is the most prevalent form of dementia and is characterized by progressive memory loss and cognitive decline. The underlying mechanism of AD has not been fully understood. At present there is no method to detect AD at its early stage. Recent studies indicate that mitochondria dysfunction is related to AD pathogenesis. Altered mitochondria functions are found in AD and influence both amyloid-β (Aβ) and tau pathology. Variations in mitochondria DNA (mtDNA) lead to a change in energy metabolism in the brain and contribute to AD. MtDNA can reflect the status of mitochondria and therefore play an essential role in AD. In this review, we summarize the changes in mtDNA and mtDNA mutations in AD patients and discuss the possibility of mtDNA being a biomarker for the early diagnosis of AD.

Keywords: Alzheimer’s disease; biomarker; mitochondria DNA

DOI: https://doi.org/10.3390/genes13101789

Front Genet. 2022 ;13 951185

Pathogenic mitochondrial DNA 3243A>G mutation: From genetics to phenotype.

Danyang Li, Chunmei Liang, Tao Zhang, Jordan Lee Marley, Weiwei Zou, Muqing Lian, Dongmei Ji.

The mitochondrial DNA (mtDNA) m.3243A>G mutation is one of the most common pathogenic mtDNA variants, showing complex genetics, pathogenic molecular mechanisms, and phenotypes. In recent years, the prevention of mtDNA-related diseases has trended toward precision medicine strategies, such as preimplantation genetic diagnosis (PGD) and mitochondrial replacement therapy (MRT). These techniques are set to allow the birth of healthy children, but clinical implementation relies on thorough insights into mtDNA genetics. The genotype and phenotype of m.3243A>G vary greatly from mother to offspring, which compromises genetic counseling for the disease. This review is the first to systematically elaborate on the characteristics of the m.3243A>G mutation, from genetics to phenotype and the relationship between them, as well as the related influencing factors and potential strategies for preventing disease. These perceptions will provide clarity for clinicians providing genetic counseling to m.3243A>G patients.

Keywords: fertility counseling; genetics; heteroplasmy; m.3243A>G; phenotype

DOI: https://doi.org/10.3389/fgene.2022.951185

HGG Adv. 2023 Jan 12. 4(1): 100148

A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.

Cameron Young, Dominyka Batkovskyte, Miyuki Kitamura, Maria Shvedova, Yutaro Mihara, Jun Akiba, Wen Zhou, Anna Hammarsjö, Gen Nishimura, Shuichi Yatsuga, Giedre Grigelioniene, Tatsuya Kobayashi.

Mitochondrial diseases are a heterogeneous group of genetic disorders caused by pathogenic variants in genes encoding gene products that regulate mitochondrial function. These genes are located either in the mitochondrial or in the nuclear genome. The TOMM7 gene encodes a regulatory subunit of the translocase of outer mitochondrial membrane (TOM) complex that plays an essential role in translocation of nuclear-encoded mitochondrial proteins into mitochondria. We report an individual with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Analysis of mouse models strongly suggested that the identified variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with homozygous Tomm7 deletion. These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver. These mice die prematurely following a rapidly progressive weight loss during the last week of their lives. Tomm7 deficiency causes a unique alteration in mitochondrial function; despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis without impairing the function of the tricarboxylic cycle metabolism or ETC. This study presents evidence that a hypomorphic variant in one of the genes encoding a subunit of the TOM complex causes mitochondrial disease.

Keywords: TOM; TOMM7; developmental delay; fatty liver; growth plate; lipoatrophy; mitochondria; mouse model; skeletal dysplasia; translocase

DOI: https://doi.org/10.1016/j.xhgg.2022.100148

Cell Death Differ. 2022 Oct 26.

Visualization of BOK pores independent of BAX and BAK reveals a similar mechanism with differing regulation.

Raed Shalaby, Arzoo Diwan, Hector Flores-Romero, Vanessa Hertlein, Ana J Garcia-Saez.

BOK is a poorly understood member of the BCL-2 family of proteins that has been proposed to function as a pro-apoptotic, BAX-like effector. However, the molecular mechanism and structural properties of BOK pores remain enigmatic. Here, we show that the thermal stability and pore activity of BOK depends on the presence of its C-terminus as well as on the mitochondrial lipid cardiolipin. We directly visualized BOK pores in liposomes by electron microscopy, which appeared similar to those induced by BAX, in line with comparable oligomerization properties quantified by single molecule imaging. In addition, super-resolution STED imaging revealed that BOK organized into dots and ring-shaped assemblies in apoptotic mitochondria, also reminiscent of those found for BAX and BAK. Yet, unlike BAX and BAK, the apoptotic activity of BOK was limited by partial mitochondrial localization and was independent of and unaffected by other BCL-2 proteins. These results suggest that, while BOK activity is kept in check by subcellular localization instead of interaction with BCL-2 family members, the resulting pores are structurally similar to those of BAX and BAK.

DOI: https://doi.org/10.1038/s41418-022-01078-w

Innovation (Camb). 2022 Nov 08. 3(6): 100329

Direct evidence of CRISPR-Cas9-mediated mitochondrial genome editing.

Rui Bi, Yu Li, Min Xu, Quanzhen Zheng, Deng-Feng Zhang, Xiao Li, Guolan Ma, Bolin Xiang, Xiaojia Zhu, Hui Zhao, Xingxu Huang, Ping Zheng, Yong-Gang Yao.

Pathogenic mitochondrial DNA (mtDNA) mutations can cause a variety of human diseases. The recent development of genome-editing technologies to manipulate mtDNA, such as mitochondria-targeted DNA nucleases and base editors, offer a promising way for curing mitochondrial diseases caused by mtDNA mutations. The CRISPR-Cas9 system is a widely used tool for genome editing; however, its application in mtDNA editing is still under debate. In this study, we developed a mito-Cas9 system by adding the mitochondria-targeted sequences and 3' untranslated region of nuclear-encoded mitochondrial genes upstream and downstream of the Cas9 gene, respectively. We confirmed that the mito-Cas9 system was transported into mitochondria and enabled knockin of exogenous single-stranded DNA oligonucleotides (ssODNs) into mtDNA based on proteinase and DNase protection assays. Successful knockin of exogenous ssODNs into mtDNA was further validated using polymerase chain reaction-free third-generation sequencing technology. We also demonstrated that RS-1, an agonist of RAD51, significantly increased knockin efficiency of the mito-Cas9 system. Collectively, we provide direct evidence that mtDNA can be edited using the CRISPR-Cas9 system. The mito-Cas9 system could be optimized as a promising approach for the treatment of mitochondrial diseases caused by pathogenic mtDNA mutations, especially those with homoplasmic mtDNA mutations.

Keywords: mitochondrial disease; mtDNA editing, mito-Cas9; third-generation sequencing

DOI: https://doi.org/10.1016/j.xinn.2022.100329