Mitochondrial diseases are an eclectic family of genetic disorders that compromise mitochondrial energy production. In many cases, the precise genetic defect causing mitochondrial dysfunction is known, but the downstream pathological outcomes for the mitochondrially diseased cell remain poorly understood. Patients experience a variety of symptoms affecting the central nervous system, muscles, heart and other tissues, and are also more susceptible to infections, particularly of the respiratory tract. The basis for this susceptibility has not been studied and is not understood.
To understand the influence of mitochondrial disease on susceptibility to microbial pathogens, this study examines Legionella infections in Dictyostelium amoebae. The authors show that, early during infection, Legionella-containing vacuoles associate with host cell mitochondria in Dictyostelium, as in human macrophages. For the first time, they show that this early association is followed by colocalization of proteins from the Legionella and the host cell mitochondria, suggesting that proteins are actively exported from Legionella into the host mitochondria. Cells with affected mitochondria show enhanced intracellular proliferation of Legionella, which is independent of pathogen uptake. This study also shows that the enhanced proliferation of Legionella inside mitochondrially diseased cells is dependent on chronic AMP-activated protein kinase (AMPK) signalling. AMPK is activated when cellular energy consumption outstrips production. The activated kinase inhibits many cellular energy-consuming activities and stimulates mitochondrial biogenesis and ATP production. The enzyme homeostatically regulates cellular energy status in a healthy cell, but in a mitochondrially diseased cell, chronic hyperactivity contributes to pathology. These results are consistent with previous data showing that mitochondrial dysfunction in Dictyostelium induces cytopathology by chronically activating AMPK. Importantly, Legionella multiplication is stimulated by hyperexpression of an active form of AMPK, which mimics the effects of mitochondrial dysfunction on this process. Conversely, genetic inhibition of AMPK expression suppresses the Legionella growth characteristic in mitochondrially diseased host cells.
This is the first report that Legionella-containing vacuoles recruit mitochondria in infected Dictyostelium cells. Future work should determine whether this association requires active pathogen functions, as it does in other hosts, and whether pathogen proteins are exported into the mitochondria. It is not known why human mitochondrial disease patients are more susceptible to microbial infections, but this study reveals that mitochondrially diseased Dictyostelium cells are more supportive of Legionella proliferation than healthy cells. This is at least partially because of chronic AMPK signalling. Future research should determine whether this is true also for human and mouse macrophages and whether, in the mouse, AMPK signaling induces susceptibility to respiratory disease from Legionella infections. Enhanced Legionella proliferation is just one of several diverse cytopathological outcomes of AMPK activity in Dictyostelium mitochondrial disease. Thus, AMPK signalling pathways may provide drug targets for the management of these currently untreatable genetic disorders.
