Advancing deep variant phenotyping of mitochondrial enzyme complexes for precision medicine in allogeneic hematopoietic stem-cell transplantation

Q4 Medicine
Jing Dong , Michael T. Zimmermann , Neshatul Haque , Shahram Arsang-Jang , Wael Saber , Xiaowu Gai , Raul Urrutia
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引用次数: 0

Abstract

Allogeneic hematopoietic stem-cell transplantation (allo-HCT), an early developed methodology for precision medicine, remains the only curative therapy for myelodysplastic syndromes (MDS). However, allo-HCT carries significant risks of morbidity and mortality due to relapse and transplant-related complications. Recurrent mutations in mitochondrial DNA (mtDNA) have been identified as significant prognostic indicators for MDS outcomes following allo-HCT. However, the biological mechanisms of mtDNA mutations remain unclear. Thus, here we performed deep variant phenotyping by integrating computational biophysics and structural genomics approaches to reveal the molecular mechanisms underlying mtDNA variant dysfunction. This emerging genomics discipline employs structural models, molecular mechanic calculations, and accelerated molecular dynamic simulations to analyze gene products, focusing on their structures and motions that determine their function. We applied this methodology on the variants in the mitochondria-encoded complex I genes that are associated with MDS pathobiology and prognosis after allo-HCT. Our results demonstrate that this approach significantly outperforms conventional analytical methods, providing enhanced and more accurate information to support the potential pathogenicity of these variants and better infer their dysfunctional mechanisms. We conclude that the adoption and further expansion of computational structural genomics approaches, as applied to the mitochondrial genome, have the potential to significantly increase our understanding of molecular mechanisms underlying the disease. Our study lays a foundation for translating mitochondrial biology into clinical applications, which will advance the integration of precision medicine with allo-HCT.
推进线粒体酶复合物的深度变异表型分析,为异基因造血干细胞移植的精准医学提供依据
同种异体造血干细胞移植(allo-HCT)是一种早期发展的精准医学方法,仍然是治疗骨髓增生异常综合征(MDS)的唯一治疗方法。然而,由于复发和移植相关并发症,同种异体hct具有显著的发病率和死亡率风险。线粒体DNA (mtDNA)的复发性突变已被确定为异基因hct后MDS结果的重要预后指标。然而,mtDNA突变的生物学机制尚不清楚。因此,在这里,我们通过整合计算生物物理学和结构基因组学方法来进行深度变异表型分析,以揭示mtDNA变异功能障碍的分子机制。这门新兴的基因组学学科采用结构模型、分子力学计算和加速分子动力学模拟来分析基因产物,重点研究决定其功能的结构和运动。我们将这种方法应用于线粒体编码复合体I基因的变异,这些基因与异基因hct后MDS的病理生物学和预后相关。我们的研究结果表明,这种方法明显优于传统的分析方法,提供了增强和更准确的信息来支持这些变异的潜在致病性,并更好地推断它们的功能失调机制。我们的结论是,计算结构基因组学方法的采用和进一步扩展,如应用于线粒体基因组,有可能显著增加我们对疾病分子机制的理解。我们的研究为线粒体生物学转化为临床应用奠定了基础,将推动精准医学与同种异体hct的融合。
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来源期刊
Transplantation Reports
Transplantation Reports Medicine-Transplantation
CiteScore
0.60
自引率
0.00%
发文量
24
审稿时长
101 days
期刊介绍: To provide to national and regional audiences experiences unique to them or confirming of broader concepts originating in large controlled trials. All aspects of organ, tissue and cell transplantation clinically and experimentally. Transplantation Reports will provide in-depth representation of emerging preclinical, impactful and clinical experiences. -Original basic or clinical science articles that represent initial limited experiences as preliminary reports. -Clinical trials of therapies previously well documented in large trials but now tested in limited, special, ethnic or clinically unique patient populations. -Case studies that confirm prior reports but have occurred in patients displaying unique clinical characteristics such as ethnicities or rarely associated co-morbidities. Transplantation Reports offers these benefits: -Fast and fair peer review -Rapid, article-based publication -Unrivalled visibility and exposure for your research -Immediate, free and permanent access to your paper on Science Direct -Immediately citable using the article DOI
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