High-Mobility Group Box 1 Is Essential for Mitochondrial Quality Control

SummaryMitochondria are organelles centrally important for bioenergetics as well as regulation of apoptotic death in eukaryotic cells. High-mobility group box 1 (HMGB1), an evolutionarily conserved chromatin-associated protein which maintains nuclear homeostasis, is also a critical regulator of mitochondrial function and morphology. We show that heat shock protein beta-1 (HSPB1 or HSP27) is the downstream mediator of this effect. Disruption of the HSPB1 gene in embryonic fibroblasts with wild-type HMGB1 recapitulates the mitochondrial fragmentation, deficits in mitochondrial respiration, and adenosine triphosphate (ATP) synthesis observed with targeted deletion of HMGB1. Forced expression of HSPB1 reverses this phenotype in HMGB1 knockout cells. Mitochondrial effects mediated by HMGB1 regulation of HSPB1 expression serve as a defense against mitochondrial abnormality, enabling clearance and autophagy in the setting of cellular stress. Our findings reveal an essential role for HMGB1 in autophagic surveillance with important effects on mitochondrial quality control.

Graphical AbstractFigure optionsDownload high-quality image (296 K)Download as PowerPoint slideHighlights
► HMGB1 sustains cellular bioenergetics and mitochondrial morphology
► Lack of HSPB1 recapitulates the HMGB1-deficient metabolic phenotype
► HSPB1 expression rescues alterations in metabolic phenotype of HMGB1 knockout cells
► HMGB1 and HSPB1 regulate mitochondrial autophagy after mitochondrial injury