Depletion of mitochondrial inorganic polyphosphate ( polyP) in mammalian cells causes metabolic shift from oxidative phosphorylation to glycolysis

Maria E. Solesio, Lihan Xie, Brendan McIntyre, Mathew Ellenberger, Erna Mitaishvili, Siddharth Bhadra-Lobo, Lisa F. Bettcher, Jason N. Bazil, Daniel Raftery, Ursula Jakob, Evgeny V. Pavlov

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Inorganic polyphosphate (polyP) is a linear polymer composed of up to a few hundred orthophosphates linked together by high-energy phosphoanhydride bonds, identical with those found in ATP. In mammalian mitochondria, polyP has been implicated in multiple processes, including energy metabolism, ion channels function, and the regulation of calcium signaling. However, the specific mechanisms of all these effects of polyP within the organelle remain poorly understood. The central goal of this study was to investigate how mitochondrial polyP participates in the regulation of the mammalian cellular energy metabolism. To accomplish this, we created HEK293 cells depleted of mitochondrial polyP, through the stable expression of the polyP hydrolyzing enzyme (scPPX). We found that these cells have significantly reduced rates of oxidative phosphorylation (OXPHOS), while their rates of glycolysis were elevated. Consistent with this, metabolomics assays confirmed increased levels of metabolites involved in glycolysis in these cells, compared with the wild-type samples. At the same time, key respiratory parameters of the isolated mitochondria were unchanged, suggesting that respiratory chain activity is not affected by the lack of mitochondrial polyP. However, we detected that mitochondria from cells that lack mitochondrial polyP are more fragmented when compared with those from wildtype cells. Based on these results, we propose that mitochondrial polyP plays an important role as a regulator of the metabolic switch between OXPHOS and glycolysis.

Original languageEnglish (US)
Pages (from-to)1631-1646
Number of pages16
JournalBiochemical Journal
Volume478
Issue number8
DOIs
StatePublished - 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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