Abedi Sina, Yung Gregory, Atilano Shari R, Thaker Kunal, Chang Steven, Chwa Marilyn, Schneider Kevin, Udar Nitin, Bota Daniela, Kenney M Cristina
Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States of America.
Department of Neurology, Neuro-Oncology Division, University of California, Irvine CA, United States of America.
PeerJ. 2020 Oct 1;8:e9908. doi: 10.7717/peerj.9908. eCollection 2020.
Drug therapy yields different results depending on its recipient population. Cisplatin, a commonly used chemotherapeutic agent, causes different levels of resistance and side effects for different patients, but the mechanism(s) are presently unknown. It has been assumed that this variation is a consequence of differences in nuclear (n) DNA, epigenetics, or some external factor(s). There is accumulating evidence that an individual's mitochondrial (mt) DNA may play a role in their response to medications. Variations within mtDNA can be observed, and an individual's mtDNA can be categorized into haplogroups that are defined by accumulations of single nucleotide polymorphisms (SNPs) representing different ethnic populations.
The present study was conducted on transmitochondrial cytoplasmic hybrids (cybrids) that possess different maternal-origin haplogroup mtDNA from African (L), Hispanic [A+B], or Asian (D) backgrounds. Cybrids were created by fusing Rho0 ARPE-19 cells (lacking mtDNA) with platelets, which contain numerous mitochondria but no nuclei. These cybrid cells were cultured to passage five, treated with cisplatin, incubated for 48 h, then analyzed for cell metabolic activity (tetrazolium dye (MTT) assay), mitochondrial membrane potential (JC-1 assay), cytotoxicity (lactate dehydrogenase (LDH) assay), and gene expression levels for , , , and .
Results indicated that untreated cybrids with varying mtDNA haplogroups had similar relative metabolic activity before cisplatin treatment. When treated with cisplatin, (1) the decline in metabolic activity was greatest in L (27.4%, < 0.012) < D (24.86%, = 0.0001) and [A+B] cybrids (24.67%, = 0.0285) compared to untreated cybrids; (2) mitochondrial membrane potential remained unchanged in all cybrids (3) LDH production varied between cybrids (L >[A+B], = 0.0270). (4) The expression levels decreased for in L ( < 0.0001) and [A+B] ( = 0.0001) cybrids but not in D cybrids ( = 0.285); and decreased for in [A+B] cybrids ( = 0.0246) compared to untreated cybrids.
Our findings suggest that an individual's mtDNA background may be associated with variations in their response to cisplatin treatment, thereby affecting the efficiency and the severity of side effects from the treatment.
药物治疗的效果因接受人群的不同而有所差异。顺铂是一种常用的化疗药物，对不同患者会产生不同程度的耐药性和副作用，但其机制目前尚不清楚。人们认为这种差异是核（n）DNA、表观遗传学或某些外部因素不同的结果。越来越多的证据表明，个体的线粒体（mt）DNA可能在其对药物的反应中起作用。mtDNA内的变异是可以观察到的，个体的mtDNA可以被分类为单倍群，这些单倍群由代表不同种族群体的单核苷酸多态性（SNP）积累所定义。
本研究针对具有来自非洲（L）、西班牙裔[A+B]或亚洲（D）背景的不同母系起源单倍群mtDNA的线粒体细胞质杂种（cybrids）进行。通过将Rho0 ARPE-19细胞（缺乏mtDNA）与血小板融合来创建cybrids，血小板含有大量线粒体但没有细胞核。将这些cybrid细胞培养至第5代，用顺铂处理，孵育48小时，然后分析细胞代谢活性（四唑盐染料（MTT）测定）、线粒体膜电位（JC-1测定）、细胞毒性（乳酸脱氢酶（LDH）测定）以及 、 、 和 的基因表达水平。
结果表明，在顺铂处理前，具有不同mtDNA单倍群的未处理cybrids具有相似的相对代谢活性。用顺铂处理后，（1）与未处理的cybrids相比，L（27.4%， < 0.012）< D（24.86%， = 0.0001）和[A+B] cybrids（24.67%， = 0.0285）的代谢活性下降最大；（2）所有cybrids的线粒体膜电位保持不变；（3）cybrids之间的LDH产生有所不同（L > [A+B]， = 0.0270）。（4）L（ < 0.0001）和[A+B]（ = 0.0001）cybrids中的 表达水平下降，但D cybrids中未下降（ = 0.285）；与未处理的cybrids相比，[A+B] cybrids中的 下降（ = 0.0246）。
我们的研究结果表明，个体的mtDNA背景可能与其对顺铂治疗的反应差异有关，从而影响治疗的效果和副作用的严重程度。
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