The Tiger Milk Medicinal Mushroom Lignosus rhinocerus (Agaricomycetes) Mitigates Oxidative Damage in a Cellular Model Mimicking Friedreich's Ataxia

<i>Lignosus rhinocerus</i> is a medicinal mushroom that is well recognized for its diverse pharmacological properties. We evaluated the protective effects of <i>L. rhinocerus</i> ethanol fraction (LREF) in Friedreich's ataxia (FRDA) by using fibroblasts treated with L-buthionine sulfoximine (L-BSO) to induce oxidative damage to mimic the pathogenesis of the disease. Liquid chromatography-mass spectrometry (LC-MS) of LREF revealed a total of eight compounds. The compound-target gene-disease network analysis also identified that phthalic acid, citric acid, oleic acid, methyl palmitate and tryptophan, were associated with gene subunits related to potassium, sodium, and calcium ion channels. In FRDA, dysregulation of ion channels leads to mitochondrial iron accumulation and decreased activity of iron-sulfur cluster enzymes. The FRDA fibroblasts were administered LREF for 4 h, followed by 12 mM L-BSO for 24 h to induce oxidative damage. Fibroblasts treated with 2.50 &#181;M idebenone were used as positive control. Administration of LREF (15.63 to 62.50 &#181;g/mL) enhanced cell viability, superoxide dismutase (SOD) activity, and mitochondrial function and biogenesis; attenuated lactate dehydrogenase (LDH) release, excessive intracellular ROS generation and apoptosis; and modulated the expression of key metabolic genes, namely peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (<i>PPARGC1A</i>), nuclear respiratory factor 1 (<i>NRF1</i>), and transcription factor A, mitochondrial (<i>TFAM</i>). The protective effects of LREF were associated with its antioxidant properties and compounds that regulate mitochondrial function and biogenesis. Our study showed that LREF can mitigate oxidative damage induced by L-BSO in a cellular model of FRDA, which could be developed into mitochondria-targeted antioxidants.