Hunt et al. show that mitochondrial stress in Drosophila neurons activates ATF4 expression, resulting in increased L-2-hydroxyglutarate (L-2-HG) levels. Reducing L-2-HG levels improves neuronal activity, demonstrating that increased L-2-HG contributes to neuronal dysfunction.

Edited by Wilhelm JustMitochondria generate the majority of cellular ATP and are essential for neuronal function. Loss of mitochondrial activity leads to primary mitochondrial diseases and may contribute to neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Mitochondria communicate with the cell through mitochondrial retrograde signaling pathways. These signaling pathways are triggered by mitochondrial dysfunction and allow the organelle to control nuclear gene transcription. Neuronal mitochondrial retrograde signaling pathways have been identified in disease model systems and targeted to restore neuronal function and prevent neurodegeneration. In this review, we describe yeast and mammalian cellular models that have paved the way in the investigation of mitochondrial retrograde mechanisms. We then discuss the evidence for retrograde signaling in neurons and our current knowledge of retrograde signaling mechanisms in neuronal model systems. We argue that targeting mitochondrial retrograde pathways has the potential to lead to novel treatments for neurological diseases.

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Neuronal mitochondrial dysfunction causes primary mitochondrial diseases and likely contributes to neurodegenerative diseases including Parkinson's and Alzheimer's disease. Mitochondrial dysfunction has also been documented in neurodevelopmental disorders such as tuberous sclerosis complex and autism spectrum disorder. Only symptomatic treatments exist for neurodevelopmental disorders, while neurodegenerative diseases are largely untreatable. Altered mitochondrial function activates mitochondrial retrograde signalling pathways, which enable signalling to the nucleus to reprogramme nuclear gene expression. In this review, we discuss the role of mitochondrial retrograde signalling in neurological diseases. We summarize how mitochondrial dysfunction contributes to neurodegenerative disease and neurodevelopmental disorders. Mitochondrial signalling mechanisms that have relevance to neurological disease are discussed. We then describe studies documenting retrograde signalling pathways in neurons and glia, and in animal models of neuronal mitochondrial dysfunction and neurological disease. Finally, we suggest how specific retrograde signalling pathways can be targeted to develop novel treatments for neurological diseases. This article is part of the theme issue ‘Retrograde signalling from endosymbiotic organelles’.