Isoform-specific roles of SIRT2 in regulating mitochondrial gene expression

TL;DR

This study shows that different versions of the SIRT2 protein affect mitochondrial genes in distinct ways, with one version (v1) boosting genes related to energy production and mitochondrial health.

Contribution

The study reveals isoform-specific regulatory effects of SIRT2 on mitochondrial gene expression, particularly highlighting the unique role of SIRT2-v1.

Findings

SIRT2-v1 significantly upregulates Complex I subunit genes (NDUFAB1, NDUFV1, NDUFS1) compared to other isoforms.

SIRT2-v1 increases PGC-1α and MFN-2 expression, which are important for mitochondrial biogenesis and fusion.

The findings suggest SIRT2-v1 has a distinct role in regulating mitochondrial function and energy metabolism.

Abstract

Sirtuin-2 (SIRT2), a member of the NAD+-dependent deacetylase family, is a key regulator of cellular processes such as metabolism, stress response and aging. We hypothesize that SIRT2 isoforms (v1, v2, v3) exert isoform-specific regulatory effects on mitochondrial-related genes, influencing mitochondrial dynamics, energy metabolism, and cellular homeostasis. To investigate this, SH-SY5Y cells, from a neuroblastoma cell line were transfected with empty vector (EV) or SIRT2 isoforms (v1, v2, v3), and the expression of mitochondrial genes, including Complex I subunits (NDUFAB1, NDUFV1, NDUFV2, NDUFS1), mitochondrial biogenesis and energy metabolism regulators (PGC-1α, PGC-1β), and mitochondrial dynamics and morphology markers (MFN-1, MFN-2, FiS1), were analyzed using quantitative RT-PCR (QuantStudio 3 Real-Time PCR System). Results revealed that SIRT2-v1 significantly upregulated mRNA levels of NDUFAB1 (p < 0.001), NDUFV1 (p < 0.01), and NDUFS1 (p < 0.05) compared to v2 and v3. SIRT2-v1 also increased PGC-1α expression (p < 0.05), numerically increased PGC-1β expression too and MFN-2 (p < 0.01), which are vital for mitochondrial biogenesis and mitochondrial fusion. These findings highlight the isoform-specific roles of SIRT-2 in modulating mitochondrial gene expression, with SIRT2-v1 predominantly influencing Complex I and PGC-1α. This study provides insights into the distinct regulatory effects of SIRT-2 v1 isoforms on mitochondrial function and metabolic pathways, underscoring their potential therapeutic relevance in mitochondrial-associated disorders. Additionally, the differential age-related increase in SIRT2 isoforms warrants further investigation.