bims-mitper 2023-04-23 papers

Issue of 2023‒04‒23
four papers selected by
Bradley Irizarry
Thomas Jefferson University

Elife. 2023 Apr 19. pii: e87194. [Epub ahead of print]12

Are some mutations more equal than others?

Auden Cote-L'Heureux, Yogesh N K Maithania, Melissa Franco, Konstantin Khrapko.

A large-scale study of mutations in mitochondrial DNA has revealed a subset that do not accumulate with age.

Keywords: aging; duplex sequencing; genetics; genomics; mitochondrial DNA; mouse; somatic mutations

DOI: https://doi.org/10.7554/eLife.87194

BBA Adv. 2023 ;3 100076

Membrane interactions of apoptotic inhibitor Bcl-xL: What can be learned using fluorescence spectroscopy.

Alexander Kyrychenko, Alexey S Ladokhin.

Permeabilization of the mitochondrial outer membrane-a point of no return in apoptotic regulation-is tightly controlled by proteins of the Bcl-2 family. Apoptotic inhibitor Bcl-xL is an important member of this family, responsible for blocking the permeabilization, and is also a promising target for anti-cancer drugs. Bcl-xL exists in the following conformations, each believed to play a role in the inhibition of apoptosis: (i) a soluble folded conformation, (ii) a membrane-anchored (by its C-terminal α8 helix) form, which retains the same fold as in solution and (iii) refolded membrane-inserted conformations, for which no structural data are available. In this review, we present the summary of the application of various methods of fluorescence spectroscopy for studying membrane interaction of Bcl-xL, and specifically the formation of the refolded inserted conformation. We discuss the application of environment-sensitive probes, Förster resonance energy transfer, fluorescence correlation spectroscopy, and fluorescent quenching for structural, thermodynamic, and functional characterization of protein-lipid interactions, which can benefit studies of other members of Bcl-2 (e.g., Bax, BAK, Bid). The conformational switching between various conformations of Bcl-xL depends on the presence of divalent cations, pH and lipid composition. This insertion-refolding transition also results in the release of the BH4 regulatory domain from the folded structure of Bcl-xL, which is relevant to the lipid-regulated conversion between canonical and non-canonical modes of apoptotic inhibition.

Keywords: Bcl-2 proteins; Distribution analysis of depth-dependent quenching; FRET; Fluorescence correlation spectroscopy; Protein-lipid interactions

DOI: https://doi.org/10.1016/j.bbadva.2023.100076

Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00001-9. [Epub ahead of print]135 203-241

The role of the nucleolus in regulating the cell cycle and the DNA damage response.

Dharaniya Sakthivel, Alexandra Brown-Suedel, Lisa Bouchier-Hayes.

The nucleolus has long been perceived as the site for ribosome biogenesis, but numerous studies suggest that the nucleolus carefully sequesters crucial proteins involved in multiple cellular functions. Among these, the role of nucleolus in cell cycle regulation is the most evident. The nucleolus is the first responder of growth-related signals to mediate normal cell cycle progression. The nucleolus also senses different cellular stress insults by activating diverse pathways that arrest the cell cycle, promote DNA repair, or initiate apoptosis. Here, we review the emerging concepts on how the ribosomal and nonribosomal nucleolar proteins mediate such cellular effects.

Keywords: Cancer; Cell cycle; DNA damage; MDM2; Nucleolus; Nucleophosmin; Ribosomal protein; p14-ARF; p53

DOI: https://doi.org/10.1016/bs.apcsb.2023.01.001

Antioxid Redox Signal. 2023 Apr 21.

Modulation of innate immune memory dynamics by subcellular ROS.

Shuo Geng, RuiCi Lin, Yajun Wu, Jing Wang, Liwu Li.

SIGNIFICANCE: Innate immune cells adopt distinct memory states during the pathogenesis of acute and chronic inflammatory diseases. Intracellular generations of reactive oxygen species (ROS) play key roles during the programming dynamics of innate immune cells such as monocytes and macrophages.RECENT ADVANCES: ROS modulates the adaptation of innate leukocytes to varying intensities and durations of inflammatory signals, facilitates fundamental reprogramming dynamics such as priming, tolerance and exhaustion, in addition to fundamental processes of proliferation, differentiation, phagocytosis, chemotaxis, as well as expression of pro- and anti-inflammatory mediators. ROS can be generated at distinct subcellular compartments including cellular membrane, mitochondria, and peroxisome. Complex inflammatory signals may finely regulate ROS generation within distinct subcellular compartments which in turn may differentially facilitate innate memory dynamics.
CRITICAL ISSUES: Complex inflammatory signals with varying strength and durations may differentially trigger ROS generation at peroxisome, mitochondria and other subcellular organelles. Peroxisomal or mitochondrial ROS may facilitate the assembly of distinct signaling platforms involved in the programming of memory innate leukocytes. Despite the emerging connection of subcellular ROS with innate immune memory, underlying mechanisms are still not well defined.
FUTURE DIRECTIONS: Recent important discoveries linking subcellular ROS and innate memory as critically reviewed here hold novel translational relevance related to acute and chronic inflammatory diseases. Capitalizing on these novel findings, future systems studies that employ next-gen single cell dynamics analyses in response to complex inflammatory environments are urgently needed in order to comprehensively decipher the programming dynamics of innate immune memory, finely modulated by subcellular ROS.

DOI: https://doi.org/10.1089/ars.2023.0304