Oligomannuronate prevents mitochondrial dysfunction induced by IAPP in RINm5F islet cells by inhibition of JNK activation and cell apoptosis

Abstract

Background: Oligomannuronates (OM) are natural products from alginate that is frequently used as food supplement. The aim of this study was to investigate the in vitro protective effects of OM on RINm5F cells against human Islet amyloid polypeptide (IAPP) induced mitochondrial dysfunction, as well as the underlying mechanisms. Methods:In the present study, we obtained several kinds of OM with different molecular masses, and then we used RINm5F cells as a model to elucidate the involvement of JNK signal pathway in hIAPP-induced mitochondrial dysfunction in pancreatic beta cells, and the protective effects of OM are associated with its ability to attenuate the mitochondrial dysfunction. Results:Our results demonstrated that human IAPP induced mitochondrial dysfunction, as evidence by loss of ΔΨm and ATP content, and decrease in oxygen consumption and complex activities, was accompanied by JNK activation, changes in the expressions of Bcl-2 and Bax proteins, release of cytochrome c (Cyto-c) and apoptosis inducing factor (AIF) from mitochondria into cytosol. Interestingly, the human IAPP induced damage in RINm5F cells were effectively restored by co-treatment of OM. Moreover, JNK activation was required for the OM mediated changes in RINm5F cells. Conclusions:OM prevented mitochondrial dysfunction induced by human IAPP in RINm5F islet cells through JNK dependent signaling pathways.

Gasdermin D Protects Mouse Podocytes Against High-Glucose-Induced Inflammation and Apoptosis via the C-Jun N-Terminal Kinase (JNK) Pathway

“…as it regulates members of the Bcl-2 family [ 21 , 22 ]. JNK can inactivate anti-apoptotic Bcl-2 proteins and activate the mitochondrial translocation of Bax [ 23 ]. SP600125, a JNK inhibitor, downregulates the expression of p-JNK, Bax, and cleaved caspase-3, thereby blocking HG-induced apoptosis.…”

Islet amyloid toxicity: From genesis to counteracting mechanisms

“…Beta-cell lines, exposed to high hIAPP concentrations, displayed the following alterations: increased ROS (Konarkowska et al, 2005), decreased mitochondrial complexes activity (X. Liu et al, 2020) and antioxidant defenses (X.-L. Li et al, 2009), membrane potential depletion, ATP production decay, mitochondrial mass loss, and mitochondrial apoptogenic factors release (Li et al, 2011(Li et al, , 2015. Oxidative stress was also observed in cultured islets from hIAPP transgenic mice (Zraika et al, 2009) and in islets from T2D patients (Sakuraba et al, 2002).…”

“…Endogenous expression of hIAPP in mice islets, exposed to high glucose, upregulated extrinsic and intrinsic elements, such as FASR, BIM, and caspase‐3 (Subramanian et al, 2012). Incubation with high concentrations of hIAPP led to mitochondrial cytochrome c release, BAX increase, and BCL‐2 decrease in RIN‐m5F cells (X. Liu et al, 2020) and caspase‐8 enhancement in human islets (Park et al, 2014). Also, in β‐cell lines exposed to elevated concentrations of hIAPP, activation of c‐Jun N‐terminal kinase (JNK) and p38 occurred, which can activate extrinsic and intrinsic apoptosis pathways (X.‐L.…”

“…Incubation with high concentrations of hIAPP led to mitochondrial cytochrome c release, BAX increase, and BCL-2 decrease in RIN-m5F cells (X. Liu et al, 2020) and caspase-8 enhancement in human islets (Park et al, 2014). Also, in β-cell lines exposed to elevated concentrations of hIAPP, activation of c-Jun N-terminal kinase (JNK) and p38 occurred, which can activate extrinsic and intrinsic apoptosis pathways (X.-L. Li et al, 2009;Rumora et al, 2002).…”

“…Moreover, ROS are known to affect mitochondrial membrane potential and to trigger mitochondria‐associated apoptosis (Murphy, 2009). Beta‐cell lines, exposed to high hIAPP concentrations, displayed the following alterations: increased ROS (Konarkowska et al, 2005), decreased mitochondrial complexes activity (X. Liu et al, 2020) and antioxidant defenses (X.‐L. Li et al, 2009), membrane potential depletion, ATP production decay, mitochondrial mass loss, and mitochondrial apoptogenic factors release (Li et al, 2011, 2015).…”