A Non-canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver.

Liver aging is characterized by chronic inflammation and metabolic dysfunction that contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Necroptosis, a form of inflammatory cell death, is activated in aging livers, and genetic ( or mice) or pharmacological (RIPK1 inhibitor necrostatin-1s) inhibition of necroptosis attenuates liver inflammation and pathology. However, the cell type-specific role of necroptosis in liver aging remains unclear.

Investigation of Domain Interaction in the Apolipoprotein E Isoforms by HDX-MS.

Involvement of apoE4 in the pathology of Alzheimer's disease (AD) is hypothesized to arise from its unique structural properties, most importantly the interactions between the N- and C-terminal domains. However, structural understanding of the domain interaction is still lacking. Here, we use Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) to study domain interactions by measuring the effect of the C-terminal domain (CTD) on the solvent accessibility of the N-terminal domain (NTD) in both apoE3 and apoE4.

Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan.

Chronic, low-grade inflammation is a hallmark of aging and various age-related diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The prevalence of metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, increases with age and contributes to morbidity and mortality among the elderly. This study investigates the role of necroptosis, a programmed cell death pathway that promotes inflammation, in liver inflammaging and age-associated MASLD by utilizing genetic ablation models of two key necroptosis proteins, Mlkl or Ripk3.

Quantitative Assessment of Conformational Heterogeneity in Apolipoprotein E4 Using Hydrogen-Deuterium Exchange Mass Spectrometry.

Apolipoprotein E4 (apoE4) is the strongest genetic risk factor for Alzheimer's disease (AD). However, structural differences between apoE4 and the AD-neutral isoform, apoE3, still remain unclear. Recent studies suggest that apoE4 harbors intermediates.