Necrotic pyknosis is a morphologically and biochemically distinct event from apoptotic pyknosis

Abstract

Classification of apoptosis and necrosis by morphological differences has been widely used for decades. However, this usefulness of this method has been seriously questioned in recent years, mainly due to a lack of functional and biochemical evidence to interpret the morphology changes. To address this matter, we devised genetic manipulations in Drosophila to study pyknosis, a process of nuclear shrinkage and chromatin condensation that occurs in apoptosis and necrosis. By following the progression of necrotic pyknosis, we surprisingly observed a transient state of chromatin detachment from the nuclear envelope, followed by the nuclear envelope completely collapsing onto chromatin. This phenomenon led us to discover that phosphorylation of barrier-to-autointegration factor (BAF) mediates this initial separation of nuclear envelope from chromatin. Functionally, inhibition of BAF phosphorylation suppressed necrosis in both Drosophila and human cells, suggesting that necrotic pyknosis is conserved in the propagation of necrosis. In contrast, during apoptotic pyknosis the chromatin did not detach from the nuclear envelope and inhibition of BAF phosphorylation had no effect on apoptotic pyknosis and apoptosis. Our research provides the first genetic evidence supporting a morphological classification of apoptosis and necrosis through different forms of pyknosis.

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“…H&E staining within the ischemic areas ( Figure 2 A–F) revealed cell death characterized by nuclear pyknotic changes, which is thought to be attributed to the irreversible condensation of the chromatin and nucleus [ 28 ], after 90-min t-MCAO ( Figure 2 B) and p-MCAO ( Figure 2 E). Notably, accumulation of inflammatory cells, such as neutrophils, was more frequently observed in and around blood vessels after p-MCAO ( Figure 2 F,M) compared to 90-min t-MCAO ( Figure 2 C,M).…”

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“…The necrotic area was delineated manually using ImageJ software, based on conventional histopathologic features of necrosis, including elongated and pyknotic nuclei, loss of the striated cardiomyocyte structure, slight increases in color intensity, and glassy cytoplasm. 18…”

Recruitment of BAF to the nuclear envelope couples the LINC complex to endoreplication

“…This implied that Ball is required for BAF localization at the nuclear envelope, presumably by promoting BAF phosphorylation. Furthermore, muscle-specific expression of either GFP-BAF, phospho-mutant BAF, in which the phosphorylated Serine-Threonine residues in its N-terminal end have been mutated to Alanine (GFP-BAF-3A), or phospho-mimmic GFP-BAF (GFP-BAF-3D) (Hou et al, 2016) was performed. The GFP-BAF was localized at the nuclear membrane, and also in the cytoplasm, similarly to the endogenous BAF, (Fig 6 A-A''').…”