The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer

Abstract

Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt.

Mitochondria inter-organelle relationships in cancer protein aggregation

“…Recently, much attention has been given to mtUPR’s role in pathological settings such as neuronal disease and cancer, where it is considered helpful for cellular homeostasis after proteotoxic stress accumulation. Indeed, mtUPR is a very conserved pathway in cancer and is often activated in response to mitochondrial stress to sustain cancer cell growth, metabolism, and survival ( Papa and Germain, 2011 ; Jenkins et al, 2021 ; Inigo and Chandra, 2022 ). In addition, mtUPR-dependent gene expression activation is a strategy for the selective adaptation of cancer cells during the stress integrated response ( Kenny et al, 2019 ).…”

Nutritional supplements for athletes and personalization; a short review

“…For example, when the cell is under stress during development or physical exertion, protein import is accelerated and the mitochondrial unfolded protein response (UPR mt ) is activated through the upregulation of HSP60 heat shock protein, and CPN10. These proteins belong to the group of chaperones that help newly synthesized proteins to get their secondary structures and that the accumulated unfolded proteins achieve their mature configuration [14].…”

Editorial: Mitophagy and mitochondrial proteostasis in cardiovascular diseases

“…ROS may play the role of signaling molecules that transmit stress signals initiated by the activation of TLR4, but may also be responsible for mitochondrial dysfunction development as they cause proteins, lipids and DNA damage or point mutation causing acute metabolic consequences (Li et al). In response to damage from transient hypoxia or mild oxidative stress, the mitochondrial protein quality control machinery is activated to maintain the diversity and function of mitochondrial proteins through the activity of chaperones and proteases, and induction of the mitochondrial unfolded protein response (3). When damaged mitochondria cannot be repaired, they are degraded through mitophagy in a receptor-dependent or independent manner.…”

“…In response to damage from transient hypoxia or mild oxidative stress, the mitochondrial protein quality control machinery is activated to maintain the diversity and function of mitochondrial proteins through the activity of chaperones and proteases, and induction of the mitochondrial unfolded protein response ( 3 ). When damaged mitochondria cannot be repaired, they are degraded through mitophagy in a receptor-dependent or independent manner.…”