Targeting the FNIP2-SERCA2b axis improves metabolic and mitochondrial defects in Ataxia Telangiectasia

TL;DR

This study identifies a new metabolic pathway involving FNIP2 and SERCA2b that could help treat Ataxia Telangiectasia by improving mitochondrial function and reducing glycogen buildup.

Contribution

The study reveals a novel role of the FNIP2-SERCA2b axis in metabolic defects of Ataxia Telangiectasia and suggests it as a potential therapeutic target.

Findings

AT cells show widespread glycogen accumulation due to impaired glucose metabolism and mitochondrial respiration.

Inactivating FNIP2 rescues metabolic defects and improves cell survival in AT cellular models.

FNIP2 interacts with SERCA2b, and its inactivation increases cytoplasmic calcium and glucose consumption.

Abstract

Ataxia telangiectasia (AT) is a rare multisystem disorder caused by the loss of functional ATM protein, leading to immunodeficiency, cancer predisposition, neurodegeneration, diabetes, heart failure, and premature aging. Although ATM’s role as a sensor of DNA double-strand breaks (DSBs) is well established, the mechanisms underlying the diverse AT phenotypes remain incompletely understood, with evidence suggesting they extend beyond DSB sensing. Here, we uncover widespread glycogen accumulation as a key feature of AT cells and tissues, driven by dysregulated glucose metabolism and impaired mitochondrial respiration assessed with a multidimensional approach including metabolomics, flux analysis, histopathology, bioenergetic measurements, and electron tomography. These metabolic defects contribute to reduced cellular viability and premature senescence observed in AT patient-derived cells. Strikingly, inactivation of FNIP2, which controls mitochondrial respiration, partially rescues these defects in AT cellular models. We show that FNIP2 interacts with the SERCA2b calcium channel, and its inactivation enhances cytoplasmic calcium availability, stimulating mitochondrial respiration and increasing glucose consumption. This metabolic reprogramming prevents glycogen accumulation and improves survival in AT primary cells. Our findings provide novel insights into AT pathophysiology and indicate the FNIP2-SERCA2b axis as a novel potential target for mitigating the systemic effects of AT and improving outcomes in this complex disease.

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