# Nucleoside diphosphate kinase strongly promotes GDP and ADP metabolism in the cell and affects endogenous proton leak in mitochondria – the kinase is hampered by oxidative phosphorylation inhibitors

## TL;DR

This paper shows that nucleoside diphosphate kinase (NDPK) is essential for GDP metabolism in yeast mitochondria and influences mitochondrial function and proton leak.

## Contribution

The study reveals that NDPK is crucial for GDP-induced effects on mitochondrial respiration and OXPHOS.

## Key findings

- NDPK transphosphorylates GDP to ADP, which then activates oxidative phosphorylation.
- Mitochondria from NDPK-deficient yeast lack a stimulatory response to GDP.
- OXPHOS inhibitors block GDP's effects by interfering with NDPK activity.

## Abstract

Rapid GDP metabolism in mitochondria isolated from wild-type yeast is postulated. The hallmark of exogenous GDP is convergence with the effect of exogenous ADP, typically inducing oxidative phosphorylation (OXPHOS). The GDP-provoked changes in the presence of ATP, i.e. increased respiratory rate accompanied by decreased inner mitochondrial membrane electrical potential, were curtailed by OXPHOS inhibitors, such as carboxyatractyloside, which apparently merged the GDP effect with OXPHOS. However, all performed tests indicated that the response of mitochondria to GDP is indirect and involves two steps. First, GDP is transphosphorylated via nucleoside diphosphate kinase (NDPK), ATP + GDP → ADP + GTP, which is followed by ADP-induced OXPHOS. Importantly, in mitochondria isolated from mutant yeast with a deleted NDPK gene, the stimulatory effect of GDP was eliminated. Therefore, a prerequisite for GDP metabolic action is the cooperation of NDPK with the OXPHOS apparatus. This biological model can help elucidate the molecular basis of some diseases treatment, such as cancer.