Abstract
Legionella pneumophila, the causative agent of Legionnaires' disease, a severe pneumonia, injects via a type 4 secretion system (T4SS) more than 300 proteins into macrophages, its main host cell in humans. Certain of these proteins are implicated in reprogramming the metabolism of infected cells by reducing mitochondrial oxidative phosphorylation (OXPHOS) early after infection. Here. we show that despite reduced OXPHOS, the mitochondrial membrane potential (Δψm) is maintained during infection of primary human monocyte-derived macrophages (hMDMs). We reveal that L. pneumophila reverses the ATP-synthase activity of the mitochondrial FOF1-ATPase to ATP-hydrolase activity in a T4SS-dependent manner, which leads to a conservation of the Δψm, preserves mitochondrial polarization, and prevents macrophage cell death. Analyses of T4SS effectors known to target mitochondrial functions revealed that LpSpl is partially involved in conserving the Δψm, but not LncP and MitF. The inhibition of the L. pneumophila-induced 'reverse mode' of the FOF1-ATPase collapsed the Δψm and caused cell death in infected cells. Single-cell analyses suggested that bacterial replication occurs preferentially in hMDMs that conserved the Δψm and showed delayed cell death. This direct manipulation of the mode of activity of the FOF1-ATPase is a newly identified feature of L. pneumophila allowing to delay host cell death and thereby to preserve the bacterial replication niche during infection.
Highlights
Beyond their essential role in cellular bioenergetics, mitochondria are integrated into diverse signaling pathways in eukaryotic cells and perform various signaling functions, such as immune responses or cell death, as they play crucial roles in the regulation of apoptosis (Bock and Tait, 2020)
Our results identified a new virulence mechanism of L. pneumophila, namely the manipulation of the mitochondrial FOF1-ATPase to preserve the integrity of infected host cells and thereby the maintenance of the bacterial replication niches
This indicates that O2 consumption, which is predominantly driven by ATP turnover and the flow of H+ to the matrix through the mitochondrial FOF1-ATPase, is severely impaired in WT-infected human monocyte-derived macrophages (hMDMs)
Summary
Beyond their essential role in cellular bioenergetics, mitochondria are integrated into diverse signaling pathways in eukaryotic cells and perform various signaling functions, such as immune responses or cell death, as they play crucial roles in the regulation of apoptosis (Bock and Tait, 2020). FOF1-ATPase, indicated that the rate of mitochondrial respiration coupled to ATP synthesis is highly reduced in WT-infected hMDMs, compared to dotA- or non-infected cells.
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