Targeting adaptive cellular responses to mitochondrial bioenergetic deficiencies in human disease

Abstract

Mitochondrial dysfunction is increasingly appreciated as a central contributor to human disease. Oxidative metabolism at the mitochondrial respiratory chain produces ATP and is intricately tied to redox homeostasis and biosynthetic pathways. Metabolic stress arising from genetic mutations in mitochondrial genes and environmental factors such as malnutrition or overnutrition is perceived by the cell and leads to adaptive and maladaptive responses that can underlie pathology. Here, we will outline cellular sensors that react to alterations in energy production, organellar redox, and metabolites stemming from mitochondrial disease (MD) mutations. MD is a heterogeneous group of disorders primarily defined by defects in mitochondrial oxidative phosphorylation from nuclear or mitochondrial-encoded gene mutations. Preclinical therapies that improve fitness of MD mouse models have been recently identified. Targeting metabolic/energetic deficiencies, maladaptive signaling processes, and hyper-oxygenation of tissues are all strategies aside from direct genetic approaches that hold therapeutic promise. A further mechanistic understanding of these curative processes as well as the identification of novel targets will significantly impact mitochondrial biology and disease research.

Keywords: hypoxia; mTORC1; metabolism; mitochondrial disease; mitochondrial dysfunction; mitochondrial signaling; oxidative stress; reactive oxygen species; redox homeostasis.

Figure 1.. Signaling mechanisms responsive to mitochondrial bioenergetics.

Biosynthetic and energetic processes of the mitochondria enable energy-sensing mechanisms to communicate with the cell. Pyruvate, glutamine, and fatty acids supply the TCA cycle of oxidative substrates that fuel the ETC, providing energy and redox equivalents. Further, proton pumps across the ETC in coordination with ions to sustain the MMP driving electron transfer, ATP synthesis, and electron leak. Mitochondrial energy production and redox, MMP, and mtROS communicate mitochondrial integrity to the cell and is sensed by a variety of pathways such as mTORC1, ISR, MAPK, hypoxia, and mitophagy signaling.