The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

Abstract

The sirtuin (SIRT) protein family has been of major research interest over the last decades because of their involvement in aging, cancer, and cell death. SIRTs have been implicated in gene and metabolic regulation through their capacity to remove acyl groups from lysine residues in proteins in an NAD+-dependent manner, which may alter individual protein properties as well as the histone–DNA interaction. Since SIRTs regulate a wide range of different signaling cascades, a fine-tuned homeostasis of these proteins is imperative to guarantee the function and survival of the cell. So far, however, how exactly this homeostasis is established has remained unknown. Here, we provide evidence that neuronal SIRT degradation in Parkinson’s disease (PD) models is executed by autophagy rather than the proteasome. In neuronal Lund human mesencephalic (LUHMES) cells, all seven SIRTs were substrates for autophagy and showed an accelerated autophagy-dependent degradation upon 1-methyl-4-phenylpyridinium (MPP+) mediated oxidative insults in vitro, whereas the proteasome did not contribute to the removal of oxidized SIRTs. Through blockade of endogenous H2O2 generation and supplementation with the selective radical scavenger phenothiazine (PHT), we could identify H2O2-derived species as the responsible SIRT-oxidizing agents. Analysis of all human SIRTs suggested a conserved regulatory motif based on cysteine oxidation, which may have triggered their degradation via autophagy. High amounts of H2O2, however, rapidly carbonylated selectively SIRT2, SIRT6, and SIRT7, which were found to accumulate carbonylation-prone amino acids. Our data may help in finding new strategies to maintain and modify SIRT bioavailability in neurodegenerative disorders.

In-depth Analysis of the Sirtuin 5-regulated Mouse Brain Acylome using Library-free Data-Independent Acquisitions

“…Baeken et al . [78] reported that oxidative stress induced SIRTs autophagic degradation in dopaminergic neurons in in vitro PD models. The authors hypothesized that the hyper-acetylation of the proteome upon SIRT depletion could have a protective role against oxidative damage by favoring acetylation-mediated transcriptional activation and preventing lysine cross-linking with other amino acid residues or nucleic acids.…”

Mitochondrial‐Targeting Vitamin B3 Ameliorates the Phenotypes of Parkinson's Disease In Vitro and In Vivo by Restoring Mitochondrial Function

“…also reported that NAD + supplementation could be utilized in a broad spectrum of NAD + deficiency‐related pathologies, such as cancer, infection, acute injury, metabolism‐related disorders, and neurodegenerative diseases. [ 50–52 ]…”

“…Xie et al also reported that NAD + supplementation could be utilized in a broad spectrum of NAD + deficiency-related pathologies, such as cancer, infection, acute injury, metabolism-related disorders, and neurodegenerative diseases. [50][51][52] Mitochondria, as energy plants, participate in signal transmission, cell differentiation, oxidative stress reactions, and calcium homeostasis. [53] Triphenylphosphonium cation (TPP + ) is the most adopted moiety that can easily and efficiently permeate the mitochondrial inner membrane.…”

SIRT7 in the aging process

“…Oxidative damage, inflammation and high glucose levels caused senescence in endothelial cells, which was associated with a decrease in SIRT7 levels and as a result an increase in miR-335-5p levels [ 90 ]. In this regard, SIRT7, like other sirtuins, is susceptible to the effects of endogenous ROS, particularly hydrogen peroxide, which cause its carbonylation and subsequent autophagic degradation [ 91 ]. On the other hand, with the number of passages, the cultures of primary mammary epithelial cells increased the expression of SIRT7, as well as the number of cells positive for β-galactosidase and with high levels of expression of p16 INK4a and p21 CIP1 [ 92 ].…”