A Mitochondrial Polymorphism Alters Immune Cell Metabolism and Protects Mice from Skin Inflammation.

Paul Schilf,Katja Bieber,Anne Braun,Hauke Busch,Lars Hellberg,Christina E Galuska,Ralf J Ludwig,Axel Künstner,Misa Hirose,Detlef Zillikens,Beate Fuchs,Saleh M Ibrahim,Michael Olbrich,Tamás Laskay,Malte Seutter,Christian D Sadik,Christian Sina,Silvio Waschina,Jan Rupp,Kerstin J Neuschütz

doi:10.3390/ijms22031006

Abstract

Several genetic variants in the mitochondrial genome (mtDNA), including ancient polymorphisms, are associated with chronic inflammatory conditions, but investigating the functional consequences of such mtDNA polymorphisms in humans is challenging due to the influence of many other polymorphisms in both mtDNA and the nuclear genome (nDNA). Here, using the conplastic mouse strain B6-mtFVB, we show that in mice, a maternally inherited natural mutation (m.7778G > T) in the mitochondrially encoded gene ATP synthase 8 (mt-Atp8) of complex V impacts on the cellular metabolic profile and effector functions of CD4+ T cells and induces mild changes in oxidative phosphorylation (OXPHOS) complex activities. These changes culminated in significantly lower disease susceptibility in two models of inflammatory skin disease. Our findings provide experimental evidence that a natural variation in mtDNA influences chronic inflammatory conditions through alterations in cellular metabolism and the systemic metabolic profile without causing major dysfunction in the OXPHOS system.

Highlights

Mitochondrial gene variations have been reported to be associated with classical mitochondrial diseases, such as Leber’s hereditary optic neuritis (LHON) [1], and with common diseases in humans, as well as model organisms
Using B6-mtFVB mice, we revealed that the m.7778G > T gene variant led to subtle changes in mitochondrial oxidative phosphorylation (OXPHOS) functions accompanied by alterations in the systemic metabolic profile and cellular metabolism in immune cells, CD4+
To assess the impact of the natural polymorphism m.7778G > T in the mitochondrially encoded gene ATP synthase 8 (mt-Atp8) gene on mitochondrial function, liver mitochondria were isolated from B6-mtFVB and B6 mice

Summary

Introduction

Mitochondrial gene variations have been reported to be associated with classical mitochondrial diseases, such as Leber’s hereditary optic neuritis (LHON) [1], and with common diseases in humans, as well as model organisms. These include ageing and age-related diseases, neurodegenerative diseases, metabolic diseases, and chronic inflammation [2]. Direct links between specific sets of mitochondrial genome (mtDNA) variations, i.e., mitochondrial haplogroups, and functional consequences have been reported in mitochondrial disorders so-called classic mitochondrial diseases [3]. The gene Cox5b, which encodes cytochrome c oxidase subunit 5B protein of mitochondrial complex IV, plays a role in the function of a murine macrophage cell line [11] and Uqcrfs, which encodes the Rieske iron-sulfur protein (RISP) protein, an essential subunit of mitochondrial complex III, and is involved in the function of murine CD4+ T cells [12] and murine haematopoietic stem cells [13]

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