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.

Tetracycline-dependent inhibition of mitoribosome protein elongation in mitochondrial disease mutant cells suppresses IRE1α to promote cell survival

“…The maintenance of the mitochondrial proteome requires an intricate balance between the import of nuclear encoded proteins synthesized on cytosolic ribosomes, and the expression of mitochondrial encoded proteins from mitoribosomes 4 . Encoding genes for rRNA and tRNA, mtDNA also encodes 13 hydrophobic protein subunits of the electron transport chain complexes 6, 35 .…”

“…Mitochondrial diseases (MDs) are a rare, clinically heterogenous, and heritable class of diseases characterized by dysfunctional mitochondria and bioenergetic defects [1][2][3] . Mitochondria rely on proteins originating from both nuclear and mitochondrial genomes where mutations in genes of nuclear or mitochondrial DNA (mtDNA) origin can manifest these diseases [1][2][3][4][5][6] . The hallmark phenotype of MD includes bioenergetic defects resulting in cellular redox imbalance, inflammatory signaling, and tissue damage.…”

Alterations in Inflammatory Cytokines and Redox Homeostasis in LPS-Induced Pancreatic Beta-Cell Toxicity and Mitochondrial Stress: Protection by Azadirachtin

“…Metabolic stress due to increased mitochondrial dysfunction under oxidative and inflammatory conditions has been increasingly appreciated in diseases and toxicities ( Bennett et al, 2021 ). Studies have revealed mitochondrial fragmentation and mitochondrial dysfunction caused by LPS-induced inflammatory responses in vitro as well as in vivo ( Ma et al, 2018 ; Harland et al, 2020 ; Dong et al, 2021 ).…”

Organelle homeostasis: from cellular mechanisms to disease

“…Remaining on the theme of mitochondrial bioenergetics, Christopher Bennett et al. [12] focus on mutations in genes that affect OXPHOS. OXPHOS‐associated diseases can arise because of mutations in some 250 mitochondrial genes, affecting one in 5000 newborns [12].…”

“…Remaining on the theme of mitochondrial bioenergetics, Christopher Bennett et al [12] focus on mutations in genes that affect OXPHOS. OXPHOSassociated diseases can arise because of mutations in some 250 mitochondrial genes, affecting one in 5000 newborns [12]. These syndromes currently have a poor treatment prognosis, which has been hampered by their nuanced phenotypic heterogeneity and designation as 'rare' disorders, as well as an incomplete understanding of the underlying biology.…”