A dynamic actin-dependent nucleoskeleton and cell identity

Abstract

Actin is an essential regulator of cellular functions. In the eukaryotic cell nucleus, actin regulates chromatin as a bona fide component of chromatin remodeling complexes, it associates with nuclear RNA polymerases to regulate transcription and is involved in co-transcriptional assembly of nascent RNAs into ribonucleoprotein complexes. Actin dynamics are therefore emerging as a major regulatory factor affecting diverse cellular processes. Importantly, the involvement of actin dynamics in nuclear functions is redefining the concept of nucleoskeleton from a rigid scaffold to a dynamic entity that is likely linked to the 3 D organization of the nuclear genome. In this review we discuss how nuclear actin, by regulating chromatin structure through phase separation may contribute to the architecture of the nuclear genome during cell differentiation and facilitate the expression of specific gene programs. We focus specifically on mitochondrial genes and how their dysregulation in the absence of actin raises important questions about the role of cytoskeletal proteins in regulating chromatin structure. The discovery of a novel pool of mitochondrial actin that serves as “mitoskeleton” to facilitate organization of mtDNA supports a general role for actin in genome architecture and a possible function of distinct actin pools in the communication between nucleus and mitochondria.

Regulation of Mitochondrial Function by the Actin Cytoskeleton

“…Actin is mainly located at the cell membrane, but also at specific mitochondrial subpopulations (Venit et al, 2021). Interactions between mitochondria and the actin cytoskeleton link the essential functions of this organelle to a plethora of cellular physiological processes.…”

“…In yeast, the ERMES complex regulates the stability and organization of mtDNA in nucleoids in an actin-dependent manner (Boldogh and Pon, 2006); in mammals, MERCs are spatially-linked to mitochondrial nucleoids, regulating their distribution, division and active transportation by the microtubules (Lewis et al, 2016). Although the presence of actin inside mitochondria and its functional connection with mtDNA was debated for decades (Venit et al, 2021), recent super-resolution microscopy-based studies probed the presence of β-actin-containing structures inside the mitochondrial matrix (Dadsena et al, 2021). Moreover, human cells lacking β-actin showed higher sensitivity to stress caused by loss of mitochondrial membrane potential (ΔΨ) plus perturbed mtDNA mass and nucleoid organization (Xie et al, 2018), suggesting a regulatory role in mtDNA transcription and quality control.…”

HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy

“…As previously discussed HDAC6 modulates actin stability ( Zhang et al, 2007 ). Actin is not only important for mitochondrial motility along with microtubules, but actin, particularly β-actin, may also play a role in mitochondrial gene expression ( Moore and Holzbaur, 2018 ; Reyes et al, 2011 ; Venit et al, 2021 ). Cortactin, when hypoacetylated, can lead to actin instability and thus may alter mitochondrial motility and function ( Zhang et al, 2007 ).…”

Cofilin and Neurodegeneration: New Functions for an Old but Gold Protein

“…For many years, the location of actin was open to debate since actin did not present a nuclear localization sequence and, therefore, presence in this organelle was assigned to cytosolic contamination caused due to its high expression levels. Many subsequent studies confirmed that the presence of actin in the nucleus was indeed real and that it even had a very relevant role in transcription and transcriptional regulation through a sophisticated mechanism in eukaryotic cells (for a review see [ 69 ]). Cells can reach a high level of gene expression regulation by tuning the state and levels of actin.…”