Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na⁺-Cl^– cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown.

We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive ²²Na⁺ transport.

Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake.

Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.

Gitelman 综合征是最常见的遗传性失盐性肾小管病，其特征是低钾性碱中毒和低镁血症。Gitelman 综合征由 SLC12A3 中的双等位基因致病变异引起，编码在远曲小管中表达的Na ⁺ -Cl ^{-协同转运蛋白 (NCC)。}CLCNKB、HNF1B、FXYD2或KCNJ10的致病变异可能导致与 Gitelman 综合征相同的肾脏表型，因为它们可导致 NCC 活性降低。大约 10% 的 Gitelman 综合征表型患者的基因型未知。

我们在三个具有 Gitelman 样电解质异常的家族中鉴定了线粒体 DNA (mtDNA) 变异，然后调查了 156 个家族的MT-TI和MT-TF变异，它们编码苯丙氨酸和异亮氨酸的转移 RNA。在患者成纤维细胞中评估线粒体呼吸链功能。^{在表达 NCC 的 HEK293 细胞中诱导线粒体功能障碍，以评估对噻嗪类敏感性22} Na ⁺转运的影响。

遗传调查揭示了 13 个家族中的四种 mtDNA 变异：m.591C>T（n = 7）、m.616T>C（n = 1）、m.643A>G（n = 1）（均在MT-TF中）、和 m.4291T>C（n = 4，在MT-TI中）。变异在受影响的个体中接近同质。所有变异都被归类为致病性，除了 m.643A>G，它被归类为意义不明的变异。重要的是，六个具有MT-TF变异的家庭的受影响成员还患有进行性慢性肾病。在患者成纤维细胞中发现氧化磷酸化复合物 IV 功能障碍和最大线粒体呼吸能力降低。体外复合物 IV 的药理学抑制模拟了 mtDNA 变体的作用，抑制了 NCC 磷酸化和 NCC 介导的钠摄取。

MT-TF和MT-TI中的致病性 mtDNA 变异可导致 Gitelman 样综合征。对于不明原因的 Gitelman 综合征样肾小管病患者，应考虑对 mtDNA 进行遗传学检查。