Background/Purpose: Primary Sjögren’s disease (pSjD) is a systemic autoimmune disease characterized mainly by immune-mediated damage to exocrine glands. Previously, we found decreased expression of ATG5 and Beclin along with increased p62 protein levels in labial salivary glands (LSG) of SjD patients, suggesting decreased macroautophagy1, which may contribute to the pathogenesis. On the other hand, recent evidence suggests that SjD is strongly associated with mitochondrial dysfunction, which may be related to inflammation as well as chronic fatigue, present in 70% of SjD patients. The increased presence of swollen mitochondria with membrane disorganization has been observed in salivary epithelial cells from SjD patients2, suggesting reduced clearance by mitophagy. The aim of this study was to determine the levels of mitophagy markers in LSG from pSjD patients.

Methods: SGs from pSjD patients (n=9) and controls (n=5) were analyzed. Mitochondrial ultrastructure was observed by transmission electron microscopy (TEM). Protein levels of mitophagy markers of the PINK-Parkin-dependent pathway (pPINK, PINK, pParkin, Parkin), -independent pathway (BNIP3L) and LC3 were determined by Western blot. The localization of LC3 and mitochondrial markers was determined by immunofluorescence. In human salivary cells stimulated with pro-inflammatory cytokines, mitochondrial ultrastructure was evaluated by TEM.

Results: LSGs from pSjD patients showed increased protein levels of PINK and pPINK and decreased protein levels of p-Parkin, Parkin and BNIP3L. In addition, LC3-II was decreased. Increased PINK protein levels suggest mitochondrial damage because this protein accumulates when mitochondria lose their membrane potential; however, Parkin, pParkin, and BNIP3L are decreased, suggesting that the canonical and alternative pathways of mitophagy are reduced in LSG of SjD patients. The COXIV staining pattern by immunofluorescence showed a more fragmented mitochondrial network in SjD patients, consistent with smaller mitochondria observed by TEM. Pro-inflammatory cytokines such as IL-1β induced an increase in the presence of mitochondria altered with myelin-like figures inside.

Conclusion: In LSG samples, we identified the major markers related to mitophagy and found that PINK Parkin-dependent and -independent pathways are decreased in LSG of pSjD patients. Reduced mitophagy could explain the presence of more fragmented and damaged mitochondria. In vitro results show that some pro-inflammatory cytokines such as IL-1β could induce important structural changes in mitochondria, supporting the idea of a link between inflammation and mitochondrial damage. The results of this work contribute to the understanding of the altered mechanisms in pSjD and raise the idea of evaluating future innovative therapies aimed at improving mitophagy, mitochondrial morphology and functionReferences:1. Rheumatology (Oxford). 2021 Apr 6;60(4):1951-1962.doi:10.1093/rheumatology/keaa670.2. Autoimmun Rev. 2021 Aug;20(8):102867. doi: 10.1016/j.autrev.2021.102867.Acknowledgments: Fondecyt-1241526/Fondecyt-1230852/Fondecyt-1210055.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/reduced-mitophagy-in-salivary-glands-of-sjogrens-disease-patients-is-associated-with-mitochondrial-structural-damage/