Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease

Abstract

Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPRmt and UPRcyt) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPRcyt responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPRmt and UPRcyt pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging.

The synthetic oleanane triterpenoid CDDO‐2P‐Im binds GRP78/BiP to induce unfolded protein response‐mediated apoptosis in myeloma

“…Here we show GRP78/BiP is a direct target of 2P‐Im in MM cells. Although prior studies have shown the third generation SOT, CDDO‐Methyl Ester (CDDO‐Me), can induce the UPR, and that inhibition of the UPR abrogates the induction of apoptosis by CDDO‐Me [27,28], the data presented here provide the first demonstration of a specific mechanism through which an SOT activates the UPR. CDDO‐2P‐Im induced apoptosis of human MM at nanomolar concentrations, and acted synergistically with the PI ixazomib, a second‐generation oral PI for the treatment of MM while being more tolerable compared with first generation PI [29].…”

The Role of Lonp1 on Mitochondrial Functions during Cardiovascular and Muscular Diseases

“…Lon protease has a significant influence on the aging process [ 147 , 148 , 149 ]. Reports have shown that deleting Pim1 in S. cerevisiae leads to faster aging [ 150 ] and C. elegans lonp-1 mutants had significantly shorter mean lifespan than wild type worms [ 151 ]. On the other hand, its overexpression in the filamentous ascomycete Podospora anserina extends health-span and lifespan [ 152 ].…”

The Thermal Stress Coping Network of the Nematode Caenorhabditis elegans

“…Mitochondrial perturbation, accompanied by heat stress resistance was also observed in lonp-1 deficient C. elegans mutants [ 128 ]. LONP-1 is the worm homolog of human LonP1, a highly conserved mitochondrial protease that functions as a peptidase, a chaperone and a DNA-binding protein, thereby fulfilling its role as a central regulator of mitochondrial activity [ 129 ].…”

“…In our recent study, we created a lonp-1 knockout C. elegans strain and showed that despite the disturbed mitochondrial function and impaired growth, fertility and lifespan in the mutant animals, there was a robust induction of both mitochondrial unfolded protein response (UPR mt ) and cytosolic HSR. Therefore, the lonp-1 mutant strain was significantly more thermotolerant compared to wild-type, even with the use of slightly aged (day 3 of adulthood) individuals [ 128 ]. However, the responsible factors and mechanisms, or the interplay between them, remains unclear.…”