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. 2020 Aug;112(8):222-237.
doi: 10.1111/boc.201900104. Epub 2020 May 7.

Insights into the functional aspects of poly(ADP-ribose) polymerase-1 (PARP-1) in mitochondrial homeostasis in Dictyostelium discoideum

Ashlesha Kadam  1 , Tina Jubin  1 , Rittwika Roychowdhury  1 , Abhishek Garg  1 , Nishant Parmar  1 , Sayantani Pramanik Palit  1 , Rasheedunnisa Begum  1
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Insights into the functional aspects of poly(ADP-ribose) polymerase-1 (PARP-1) in mitochondrial homeostasis in Dictyostelium discoideum

Ashlesha Kadam et al. Biol Cell. 2020 Aug.

Abstract

Background information: Poly(ADP-ribose) Polymerase-1 (PARP-1) is predominantly a nuclear protein and involved in various cellular processes like DNA repair, cell death, development, chromatin modulation etc. PARP-1 utilizes NAD+ and adds negatively charged PAR moieties on the target proteins. Over-activation of PARP-1 has been shown to cause energy crisis mediated cell death in which mitochondrial homeostasis is also affected. Moreover, the presence of mitochondrial NAD+ pools highlights the role of PARP-1 in mitochondria. The aim of present study is to understand the physiological role of PARP-1 in regulating mitochondrial functioning by varying the levels of PARP-1 in Dictyostelium discoideum. Intra-mitochondrial PARylation was analyzed by indirect immunofluorescence. Further, the effect of altered levels of PARP-1 i.e. overexpression, downregulation, knockout and its chemical inhibition was studied on mitochondrial respiration, reactive oxygen species (ROS) levels, ATP production, mitochondrial fission-fusion, mitochondrial morphology and mitochondrial DNA (mtDNA) content of D. discoideum.

Results: Our results show intra-mitochondrial PARylation under oxidative stress. Altered levels of PARP-1 caused impairment in the mitochondrial respiratory capacity, leading to elevated ROS levels and reduced ATP production. Moreover, PARP-1 affects the mitochondrial morphology and mtDNA content, alters the mitochondrial fission-fusion processes in lieu of preventing cell death under physiological conditions.

Conclusion: The current study highlights the physiological role of PARP-1 in mitochondrial respiration, its morphology, fission-fusion processes and mtDNA maintenance in D. discoideum.

Significance: This study would provide new clues on the PARP-1's crucial role in mitochondrial homeostasis, exploring the therapeutic potential of PARP-1 in various mitochondrial diseases.

Keywords: Dictyostelium discoideum; Fission-fusion; Mitochondrial respiration; Poly(ADP-ribose) polymerase-1; Reactive oxygen species.

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References

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