Lysine deacetylases and mitochondrial dynamics in neurodegeneration

• Type: Another Publication in an International Scientific Journal
• Date: 2013

Authors

Pedro Guedes-Dias (Author) FFUP; Jorge M A Oliveira (Author) FFUP

Journal

Title: Biochimica et Biophysica Acta - Molecular Basis of Disease

Vol. 1832

Pages: 1345-1359

ISSN: 0925-4439

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 31 Citations

Scopus - 42 Citations

Scientific classification

CORDIS: Health sciences > Neuroscience

FOS: Natural sciences > Biological sciences

Associated Projects

KDAC´S - Inibição de KDACs e dinâmica intracelular: impacto no desenvolvimento, sobrevivência e transmissão NEUROnal

Other information

Authenticus ID: P-006-8W7

DOI: 10.1016/j.bbadis.2013.04.005

Abstract (EN): Lysine acetylation is a key post-translational modification known to regulate gene transcription, signal transduction, cellular transport and metabolism. Lysine deacetylases (KDACs), including classical KDACs (a.k.a. histone deacetylases; HDACs) and sirtuins (SIRTs), are emerging therapeutic targets in neurodegeneration. Given the strong link between abnormal mitochondrial dynamics and neurodegenerative disorders (e.g. in Alzheimer, Parkinson and Huntington diseases), here we examine the evidence for KDAC-mediated regulation of mitochondrial biogenesis, fission-fusion, movement and mitophagy. Mitochondrial biogenesis regulation was reported for SIRT1, SIRT3, and class IIa KDACs, mainly via PGC-1alpha modulation. SIRT1 or SIRT3 overexpression rescued mitochondrial density and fission-fusion balance in neurodegeneration models. Mitochondrial fission decreased with pan-classical-KDAC inhibitors and increased with nicotinamide (pan-sirtuin-inhibitor/activator depending on concentration and NAD(+) conversion). Mitochondrial movement increased with HDAC6 inhibition, but this is not yet reported for the other tubulin deacetylase SIRT2. Inhibition of HDAC6 or SIRT2 was reported neuroprotective. Mitophagy is assisted by the HDAC6 ubiquitin-binding and autophagosome-lysosome fusion promoting activities, and was also associated with SIRT1 activation. In summary, KDACs can potentially modulate multiple components of mitochondrial dynamics, however, several key points require clarification. The SIRT1-biogenesis connection relies heavily in controversial caloric restriction (CR) regimes or CR-mimetic drugs, and appears cell-type dependent, recommending caution before linking SIRT1 activation with general neuroprotection. Future studies should clarify mitochondrial fission-fusion regulation by KDACs, and the interplay between HDAC6 and SIRT1 in mitophagy. Also, further studies are required to ascertain whether HDAC6 inhibition to enhance mitochondrial trafficking does not compromise autophagy or clearance of misfolded proteins in neurodegenerative disorders.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15