Zhenyu Zhong

Congrats to all awardees!

Grateful to our wonderful collaborators and outstanding lab members👍 and for support from UTSW, CPRIT, and NIH🙏

Bottom line: obesity renders an existing metabolic brake dysfunctional, allowing NLRP3 activation to proceed unchecked. Targeting nucleotide metabolism may help cool obesity-driven inflammation and thereby prevent/treat obesity-associated diseases.

Obesity therefore rewires the mitochondrial nucleotide supply chain: from regulated CMPK2-driven salvage synthesis to unrestrained PNC1/2-mediated nucleotide mitochondrial import, causing excessive mtDNA neosynthesis, ox-mtDNA production and lower threshold for NLRP3 activation.

New mitochondrial DNA synthesis enables NLRP3 inflammasome activation - Nature New mitochondrial DNA synthesis links the priming and activation of the NLRP3 inflammasome.

Importantly, this bypasses the CMPK2-dependent mitochondrial dNTP salvage pathway that we previously showed is essential for NLRP3 activation in macrophages under healthy conditions (nature.com/articles/s41...).

When SAMHD1 becomes dysfunctional, dNTPs accumulate and are transported into mitochondria via the nucleotide carriers PNC1/2, driving excessive mitochondrial DNA synthesis and damage.

This is not due to increased expression of inflammasome components. Instead, obesity disables SAMHD1, an enzyme that normally restrains intracellular dNTP pools.

Macrophages from obese humans and mice show hyperactive NLRP3 inflammasome signaling, producing excess IL-1β relative to those from lean subjects.

Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain–containing 3 (NLRP3) inflammasome hyperactivation and e...

Why is obesity often associated with dysregulated, low-grade chronic inflammation?
In our new paper in @science.org we show that obesity rewires nucleotide metabolism in immune cells, making inflammatory responses much easier to trigger. www.science.org/doi/10.1126/...