# Targeting MFF succinylation: a novel therapeutic strategy for premature ovarian insufficiency by restoring mitochondrial dynamics in granulosa cells

## TL;DR

This paper proposes a new therapeutic strategy for premature ovarian insufficiency by targeting MFF succinylation to restore mitochondrial function in granulosa cells.

## Contribution

The paper introduces a novel hypothesis linking MFF succinylation to mitochondrial dysfunction in POI and suggests targeting the SIRT5-MFF axis as a potential treatment.

## Key findings

- Hyper-succinylation of MFF at K302 may cause mitochondrial fragmentation and cell death in granulosa cells.
- Elevated succinyl-CoA and reduced SIRT5 activity are theorized to drive MFF succinylation in POI.
- Modulating SIRT5 activity may reverse MFF succinylation and restore mitochondrial dynamics.

## Abstract

Premature ovarian insufficiency (POI) is a significant clinical disorder characterized by the loss of ovarian function before the age of 40, and its global prevalence is rising. The development of effective therapies is hindered by an incomplete understanding of its pathogenesis. Growing evidence indicates that dysregulated mitochondrial fission in granulosa cells (GCs) is a pivotal contributor to POI, although the upstream regulatory mechanisms remain elusive. This review synthesizes recent findings to propose a novel hypothesis: that aberrant lysine succinylation (Ksucc) of mitochondrial fission factor (MFF) may act as a crucial metabolic switch linking mitochondrial dynamics to ovarian aging. Specifically, hyper-succinylation of MFF at specific residues (e.g., K302) is hypothesized to induce a charge reversal, potentially promoting the excessive recruitment and oligomerization of dynamin-related protein 1 (DRP1) on the mitochondrial membrane. We hypothesize that this leads to mitochondrial fragmentation, bioenergetic deficits, and subsequent apoptosis of GCs and oocytes. This pathogenic cascade is theorized to be driven by a metabolic milieu of elevated succinyl-CoA and diminished desuccinylase activity of SIRT5 in POI. Evidence from related disease models suggests that reversing this imbalance through genetic or pharmacological modulation of SIRT5 can reduce MFF succinylation and restore mitochondrial dynamics. We explore the potential of targeting the SIRT5-MFF axis as a promising therapeutic strategy. Furthermore, detecting elevated MFF succinylation in clinical samples may be explored as a novel diagnostic biomarker for POI, though significant translational hurdles remain.