Fdx2, a mitochondrial [2Fe-2S] ferredoxin, is crucial for Fe-S protein biogenesis in humans [1]. It is ubiquitously expressed and essential in the de novo formation of [2Fe-2S] clusters [5]. This process is involved in various metabolic pathways and overall cellular function, making Fdx2 of high biological importance. Genetic models, such as gene knockout (KO) models, can be valuable for studying its functions.

In ovarian cancer cells, conditional KO of Fdx2 led to global downregulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage, p53 pathway activation, and driving senescence, apoptosis, or ferroptosis depending on p53 status and phospholipid homeostatic activity [4]. In individuals with biallelic Fdx2 variants, there were severe and recurrent rhabdomyolyses, lactic acidosis, reduced oxygen consumption rates, and mitochondrial complex I and PDHc activities [2]. A patient with a homozygous likely pathogenic variant in Fdx2 presented with myopathy, multiple episodes of rhabdomyolysis, and lactic acidosis [3]. Also, patients with a homozygous missense mutation in Fdx2 had a complex neurological phenotype involving optic atrophy, nystagmus, myopathy, and reversible leukoencephalopathy [5].

In conclusion, Fdx2 is essential for Fe-S protein biogenesis, which impacts multiple cellular processes. Model-based research, especially KO models, has revealed its role in various disease conditions such as rhabdomyolysis, myopathy, and complex neurological phenotypes. Understanding Fdx2 functions provides insights into the underlying mechanisms of these diseases, potentially guiding future diagnostic and therapeutic strategies.