Conference Agenda

Circadian rhythms confer an evolutionary advantage by anticipating recurrent geo-physical changes optimizing metabolic function throughout the day-time. Disruption/misalignment of these rhythms is increasingly associated with various human pathologies, linking metabolic disorders to disturbances in the clock machinery. At the cellular level, time-keeping mechanisms are governed by self-sustained transcription-translation feedback loops involving well-characterized transcription factors. These clocks regulate numerous transcriptional-translational processes that influence overall cellular metabolism, particularly mitochondrial function. The expression of several genes encoding the mitochondrial OxPhos system as well as the mitochondrial respiratory activity undergo circadian oscillations though no significant changes in the content respiratory chain complexes is observed. Evidence is provided that these apparently conflicting observations can be reconciled as follows:
A) Rhythmic modulation of mitochondrial respiration is linked to reversible phosphorylation of Complex I, which controls its activity and can be traced back to the clock genes-controlled NAMPT-NAD-Sirtuin axis [1].
B) Metabolic flux upstream of the respiratory chain is temporally controlled; in particular, pyruvate oxidation is modulated by the reversible phosphorylation of the PDH complex, dependent on the oscillating in/out flux of mitochondrial Ca2+, likely derived from the ER store [2].
C) The expression of factors controlling mitochondrial biogenesis and degradation appears to oscillate under the control of clock genes in anti-phase, thus balancing organelle dynamics.
Importantly, just as the clock machinery governs mitochondrial OxPhos-related functions, mitochondrial dysfunctions, in turn, impact the clock genes-mediated oscillatory homeostasis [3]. Understanding the mechanisms intertwining mitochondrial metabolism and circadian clock-genes will provide valuable insights for developing innovative chrono-therapeutic approaches.
[1] O. Cela, R. Scrima, V. Pazienza, G. Merla, G. Benegiamo, B. Augello, S. Fugetto, M. Menga, R. Rubino, L. Fuhr, A. Relógio, C. Piccoli, G. Mazzoccoli, N. Capitanio, Clock genes-dependent acetylation of complex I sets rhythmic activity of mitochondrial OxPhos. Biochim Biophys Acta, 1863 (2016) 596-606.
[2] R. Scrima, O. Cela, F. Agriesti, C. Piccoli, T. Tataranni, C. Pacelli, G. Mazzoccoli, N. Capitanio, Mitochondrial calcium drives clock gene-dependent activation of pyruvate dehydrogenase and of oxidative phosphorylation, Biochim Biophys Acta Mol Cell Res., 1867 (2020)118815.
[3] R. Scrima, O. Cela, G. Merla, B. Augello, R. Rubino, G. Quarato, S. Fugetto, M. Menga, L. Fuhr, A. Relógio, C. Piccoli, G. Mazzoccoli, N. Capitanio, Clock-genes and mitochondrial respiratory activity: Evidence of a reciprocal interplay, Biochim Biophys Acta, 1857 (2016) 1344-1351.

Mitochondrial diseases are associated with impaired oxidative phosphorylation (OXPHOS) that leads to a wide range of severe symptoms [1, 2]. We explored whether membrane-permeant small molecules with redox cycler activities can be exploited to treat OXPHOS deficiency-related diseases. We identified a few molecules for their ability to replace the redox functions of complexes I and III. Sub-μM doses of these drugs were shown to restore respiration in mouse fibroblasts as well as in fibroblasts from patients harboring pathogenic mutations in three different assembly/stabilization factors of complex III or a subunit of complex I. Enhanced respiration by the drugs was associated with increased ATP production, normalization of the mitochondrial membrane potential, mildly increased ROS production, and augmented mitochondrial biogenesis [3]. Administration of low concentrations of the drugs significantly improved motor endurance and motor coordination in fruit fly, zebrafish and mouse models of respiratory chain complex deficiency. Recovery of function paralleled with changes in cellular signaling and metabolism. Importantly, no toxicity was observed upon long-term treatment, suggesting that redox cyclers, when used at low concentrations, may represent a therapeutic option against diseases due to OXPHOS dysfunction.

[1] C. Viscomi, M. Zeviani, Strategies for fighting mitochondrial diseases, Journal of internal medicine, 287 (2020) 665-684.

[2] A. Suomalainen, B.J. Battersby, Mitochondrial diseases: the contribution of organelle stress responses to pathology, Nature reviews. Molecular cell biology, 19 (2018) 77-92.

[3] R. Peruzzo, S. Corrà, R. Costa, M. Brischigliaro, T. Varanita, L. Biasutto, C. Rampazzo, D. Ghezzi, L. Leanza, M. Zoratti, M. Zeviani, C. De Pittà, C. Viscomi, R. Costa, I. Szabò, Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction, Nature communications, 12 (2021) 2103.

Neurodegeneration with Brain Iron Accumulation is a broad, heterogeneous group of inherited diseases, characterized by progressive symptoms associated with excessive abnormal iron deposition in the brain. In our study we focus on a particular NBIA subtype, called mitochondrial membrane protein-associated neurodegeneration (MPAN), which now seems to be the second most common NBIA subtype in the word and dominant in Poland. The disease is related to autosomal recessive or dominant mutation in C19orf12 gene encoding mitochondrial membrane protein. Interestingly, the molecular mechanism underlying MPAN as well as the role of C19orf12 protein in the pathogenesis of the disease is still not fully understood. We are investigating impaired mitochondrial and metabolic function of fibroblasts derived from patients with MPAN to identify alterations in the metabolism and look for strategies to intervene in cellular metabolism for therapeutic benefit.

Acknowledgements: The study is co-financed from the state budget from the Education and Science Ministry program entitled “Science for Society”. Project numer NdS/537386/2021/2022, the amount of co-financing 1 900 000 PLN, total value of the project 1 900 000 PLN. Poland