Mitochondrial Dysfunction and Oxidative Stress in Hereditary Ectopic Calcification Diseases

Abstract

Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC contributes to significant morbidity and mortality and is considered a major health problem for which no effective treatments currently exist. In recent years, growing emphasis has been placed on the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of EC. Impaired mitochondrial respiration and increased levels of reactive oxygen species can be directly linked to key molecular pathways involved in EC such as adenosine triphosphate homeostasis, DNA damage signaling, and apoptosis. While EC is mainly encountered in common diseases such as diabetes mellitus and chronic kidney disease, studies in rare hereditary EC disorders such as pseudoxanthoma elasticum or Hutchinson–Gilford progeria syndrome have been instrumental in identifying the precise etiopathogenetic mechanisms leading to EC. In this narrative review, we describe the current state of the art regarding the role of mitochondrial dysfunction and oxidative stress in hereditary EC diseases. In-depth knowledge of aberrant mitochondrial metabolism and its local and systemic consequences will benefit the research into novel therapies for both rare and common EC disorders.

Significance of Premature Vertebral Mineralization in Zebrafish Models in Mechanistic and Pharmaceutical Research on Hereditary Multisystem Diseases

“…Besides pathways involved in bone formation and remodeling, inflammatory pathways were also upregulated in the kl−/− mutants. More recently, it was proposed that cellular senescence contributes to the ectopic calcification and premature death of these mutants, opening the possibility of using these mutants to model (premature) aging [86][87][88].…”

Ectopic Calcification: What Do We Know and What Is the Way Forward?

“…Studies in hereditary ectopic calcification disorders have been instrumental in identifying the pathophysiological mechanisms of ectopic mineralization [17]. If a single genetic mutation can result in multisystem calcifications, identifying its exact function will help to unravel mechanisms through which the development of ectopic calcification occurs 2 of 5 in other diseases.…”

“…A loss-of-function mutation in the ABCC6 gene causes PXE. ABCC6 encodes for an adenosine triphosphate (ATP) binding efflux transporter, which facilitates the transport of ATP into the systemic circulation, where it is converted into adenosine monophosphate (AMP) and PPi by the enzyme ENPP1 [3,17,18]. A mutation in the ABCC6 gene is associated with low PPi levels [17,18].…”

“…ABCC6 encodes for an adenosine triphosphate (ATP) binding efflux transporter, which facilitates the transport of ATP into the systemic circulation, where it is converted into adenosine monophosphate (AMP) and PPi by the enzyme ENPP1 [3,17,18]. A mutation in the ABCC6 gene is associated with low PPi levels [17,18]. PPi normally directly inhibits the accumulation of calcium and phosphate, preventing hydroxyapatite crystals from forming in soft tissues [15].…”