Mitophagy protects beta cells from inflammatory damage in diabetes

Vaibhav Sidarala, Gemma L. Pearson, Vishal S. Parekh, Benjamin Thompson, Lisa Christen, Morgan A. Gingerich, Jie Zhu, Tracy Stromer, Jianhua Ren, Emma Reck, Biaoxin Chai, John A. Corbett, Thomas Mandrup-Poulsen, Leslie S. Satin, Scott A. Soleimanpour

Preprint posted on 9 June 2020

Article now published in JCI Insight at

Eating up mitochondria to shield beta-cells from inflammation-induced injury: a role for Clec16a

Selected by Giuliana Clemente

Categories: cell biology

Context and Background:

Classically known as the powerhouse of cells, mitochondria are so much more than that. These organelles are important signaling hubs that control and coordinate a variety of cellular functions, including metabolism, response to stress and cell death. Therefore, the maintenance of a healthy mitochondrial network is pivotal for survival and the signals emitted from dysfunctional mitochondria are at the origin of a variety of diseases, including cardiovascular and neurodegenerative diseases and type-1 and type-2 diabetes (TD-1 and TD-2).

Mitophagy, a specialized form of autophagy, mediates the selective removal of damaged mitochondria and preserves the homeostasis of the network. Recently, the endosomal protein Clec16a has been characterized as a new activator of mitophagy in b-cells. GWAS studies have classified Clec16a as a susceptibility gene for type 1 diabetes and SNPs in this locus have been linked to the development of diabetes. Moreover, reduced levels of Clec16a in human islets has been associated with dysfunctional b-cell activity and compromised glucose control. However, whether Clec16a (and mitophagy in general) plays any role in the defense of b-cells from inflammation-derived injury has not been explored yet.

Since the early 1950’s a causal link between inflammation and development of insulin resistance was suspected. Nowadays, it is well established that the chronic activation of pro-inflammatory signals (as the ones mediated by pro-inflammatory cytokines) predisposes to a decreased insulin sensitivity and contributes to the onset of diabetes. It is therefore important to understand the response of b-cells to inflammation and investigate whether special cytoprotective response are in place to withstand the damage.

In this preprint, Sidarala et al. identify Clec16a as an important player in the protection of b-cells from inflammatory damage through the activation of mitophagy.

Main findings:

The authors show that mitochondria of b-cells exposed to pro-inflammatory cytokines accumulate a great deal of oxidative damage, resulting in the loss of mitochondrial membrane potential, decreased oxygen consumption and a reduced ATP/ADP ratio. Given that optimal mitochondrial activity is essential for the response to glucose, healthy b-cells dispose oxidized mitochondria by activating mitophagy, preserving a healthy mitochondrial network (Figure 1, left panel). Activation of inflammation-mediated mitophagy is reversible and can be limited by withdrawal of pro-inflammatory cytokines, by inhibition of free radical generation (NOS2-/-) or by exposure to superoxide scavengers.

Activation of mitophagy is key to preserve b-cell function. Blocking mitophagy by removing the key mitophagy regulator Clec16a (b-Clec16aKO), exacerbates the inflammatory response leading to a progressive reduction in mitochondrial volume, increased mitochondria fragmentation and ultimately enhanced apoptosis (Figure 1, right panel). Consequently, b-cell death affects insulin production resulting in the exaggerated increase in blood glucose levels. The authors suggest that mitophagy is an essential protective strategy that promotes b-cell survival in response to uncontrolled oxidative stress. This conclusion is further supported by the observation that overexpression of Clec16a in human islets protects b-cells from inflammation-induced apoptosis.

Figure 1: Clec16a-mediated mitophagy prevents the onset of diabetes. Left panel: in healthy b-cells oxidized mitochondria are promptly removed by mitophagy. This cellular response is controlled by the master regulator Clec16a and it is marked by the localization of cytosolic Parkin (in blue) to damaged mitochondria. Dysfunctional, fragmented mitochondria are cleared up by proteolytic degradation in the lysosomes. This strategy preserves the integrity of the mitochondrial network and promotes cell viability. Right panel: inhibition of mitophagy increases cell susceptibility to inflammation, resulting in the aberrant accumulation of damaged mitochondria and activation of the apoptotic response. Preventing mitophagy can be propaedeutic to the development of type 1 and type 2 diabetes. Image was generated with the help of Biorender.


This preprint identifies Clec16a as important mediator of b-cell survival following inflammation. By activating mitophagy, Clec16a fine-tunes b-cell susceptibility to inflammatory stress and apoptosis and emerges as a relevant therapeutic target for the treatment of diabetes.

Questions to the authors:

  1. Immune cells have been shown to be able to transfer mitochondria to sensory neurons via extracellular vesicles. Do you think that a similar thing might happen with b-cells to replenish the pool of healthy mitochondria?
  2. Clec16a has been linked to the development of other diseases (i.e. multiple sclerosis). Do you think this protein regulates tissue homeostasis via the same mechanism (namely mitophagy) or do you think it is more of a ‘swiss army knife’?



Posted on: 23 June 2020 , updated on: 25 June 2020


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Author's response

Scott A. Soleimanpour shared

While I am unaware of evidence of horizontal mitochondrial transfer between beta cells (or other islet cell types), I certainly think the evidence is strong that this occurs in other systems. Thus, I presume that there is a potential for this to occur to replenish beta cell mitochondrial pools. It’s a fascinating question and one we are hoping to test in my lab in the coming years.

This is an excellent question. I think we are just beginning to scratch the surface of the functional interactions of Clec16a in beta cells, not to mention the cell types of relevance of other Clec16a-linked diseases, such as MS. Beautiful work from several other groups have identified binding partners beyond our recent studies on the Clec16a-Nrdp1-Usp8-Parkin mitophagy pathway, including the Vps-C HOPS complex, Rilp, and Rab2. Thus, I anticipate that Clec16a could have both overlapping and distinct functional roles to its effects in beta cells depending on the cell type of interest through these partners/effectors.

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