Parkin Coordinates Platelet Stress Response in Diabetes Mellitus: A Big Role in a Small Cell

Abstract

Increased platelet activation and apoptosis are characteristic of diabetic (DM) platelets, where a Parkin-dependent mitophagy serves a major endogenous protective role. We now demonstrate that Parkin is highly expressed in both healthy platelets and diabetic platelets, compared to other mitochondria-enriched tissues such as the heart, muscle, brain, and liver. Abundance of Parkin in a small, short-lived anucleate cell suggest significance in various key processes. Through proteomics we identified 127 Parkin-interacting proteins in DM platelets and compared them to healthy controls. We assessed the 11 highest covered proteins by individual IPs and confirmed seven proteins that interacted with Parkin; VCP/p97, LAMP1, HADHA, FREMT3, PDIA, ILK, and 14-3-3. Upon further STRING analysis using GO and KEGG, interactions were divided into two broad groups: targeting platelet activation through (1) actions on mitochondria and (2) actions on integrin signaling. Parkin plays an important role in mitochondrial protection through mitophagy (VCP/p97), recruiting phagophores, and targeting lysosomes (with LAMP1). Mitochondrial β-oxidation may also be regulated by the Parkin/HADHA interaction. Parkin may regulate platelet aggregation and activation through integrin signaling through interactions with proteins like FREMT3, PDIA, ILK, and 14-3-3. Thus, platelet Parkin may regulate the protection (mitophagy) and stress response (platelet activation) in DM platelets. This study identified new potential therapeutic targets for platelet mitochondrial dysfunction and hyperactivation in diabetes mellitus.

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

“…The inhibition of FUNDC1-induced mitophagy was found to attenuate myocardial damage during myocardial infarction by reducing thrombosis. Similarly, in the pathogenesis of diabetes mellitus, Parkin-induced mitophagy was shown to sustain platelet function, thereby increasing platelet activation and aggregation in the microcirculation ( Latacz et al, 2020 ; Lee et al, 2020 ). Thus, mitophagy can contribute to cardiovascular disorders by enhancing platelet activation and aggregation.…”

Pink1/Parkin deficiency alters circulating lymphocyte populations and increases platelet-T cell aggregates in rats

“…The highest concentration of α-synuclein per mg of cellular protein in the blood is found in platelets 65,66 . In addition to α-synuclein, platelets express various other PDrelevant proteins, including tyrosine hydroxylase 67 , dopamine transporter 68 , Pink1 69 , and Parkin 70 . Of note, we previously reported elevated levels of plasma α-synuclein in the Pink1/Parkin dKO rats 25 .…”