Mitochondrial stress in Fabry disease

Fabry disease (FD) is clinically heterogeneous. As some GLA variants attain similar levels of residual activity but result in a range of phenotypes, our aim is to understand factors influencing phenotypic variability.

The mitochondrial unfolded protein response (mtUPR) is a stress response mechanism activated by multiple forms of mitochondrial dysfunction including accumulation of misfolded protein. As mitochondrial dysfunction has been reported, we investigated intracellular levels of heat shock protein 60 (Hsp60) by western blotting in 27 FD patients: 11 N215S (7 males) and 16 non-N215S (7 males) vs 4 heathy controls (HC, 3 males and 1 female). Serum Fibroblast Growth Factor-21 (FGF21), and Growth Differentiation Factor-15 (GDF-15) were also measured. Clinical outcomes explored included the Mainz Severity Score Index (MSSI), the Age-Adjusting Severity Scores (AASS), estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI). Globotriaosylsphingosine (lyso-Gb3) data was available for a subset of participants.

Hsp60 showed no significant differences between groups (males FD: 0.29 vs HC: 0.11, females HC: 0.26 vs FD: 0.19 Hsp60/LC), however, differences among FD patients were noted. While some had over 2-fold that of HCs, others had less than half of HCs despite genotype and gender. When analysed in terms of severity scores, the N215S group with higher levels of Hsp60 corresponded with a milder phenotype. LVMI and eGFR also seemed to improve with higher levels of Hsp60 only for this group. In terms of FGF-21 and GDF-15, lower levels showed a trend with higher Hsp60 levels and LVMI in the N215S group.

To conclude, our findings suggest a potential role for mtUPR activation, as evidenced by intracellular Hsp60 levels, in modulating cardiac and renal manifestations in Fabry disease. These preliminary associations highlight the need for longitudinal studies to validate Hsp60 and mitokines as biomarkers of disease progression, aiming to inform personalized approaches that improve outcomes across Fabry disease phenotypes.