Izabella is an enthusiastic researcher, passionate about science and biology. Dr Pena is a Brazilian scientist with a PhD in Genetics and Molecular Biology and vast scientific experience (Brazil (University of Campinas), UK (SGC-University of Oxford), Canada (CHEO-RI/uOttawa) and the United States (MIT)).
Her laboratory aims to investigate molecular mechanisms of rare metabolic disorders affecting the pediatric population. She focuses on diseases where the affected gene/protein has roles in the function of an organelle called mitochondria. Examples of such diseases include Pyridoxine-Dependent Epilepsy (PDE), Glutaric Acidemia type I (GA1) and Congenital Sideroblastic Anemias (CSA).
The Pena lab uses functional genomics (CRISPR screens), organelle profiling (metabolomics and proteomics LC-MS), gene therapy (AAV), drug screenings, develop animal models and various molecular biology techniques to investigate these rare diseases. The main models of study are patient-derived cells (fibroblasts and lymphoblasts), common cell lines, zebrafish and mice. Being based at CHEO-RI, Izabella is fortunate to collaborate with clinicians and patient families to understand these diseases and try to develop new therapies.
MCART1/SLC25A51 is required for mitochondrial NAD transport
Nicotinamide adenine dinucleotide (NAD) is an essential cofactor in redox metabolism and metabolic signaling. As cofactors of metabolic enzymes, NAD+ and its reduced form, NADH, function in redox re-actions in central metabolic pathways including glycolysis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and one-carbon metabolism and control the direction of flux through these pathways. As a cosubstrate of the sirtuins and poly-(ADP-ribose) polymerases, NAD+ mediates posttranslational modification of metabolic enzymes, DNA repair and chromatin-modifying proteins, and other factors involved in stress response and signaling pathways that connect metabolism to different physiological responses (1). NAD levels decline in aging, and administration of NAD precursors is currently being tested in the clinic as a measure to prevent age-associated diseases [(2, 3); clinicaltrials.gov].
PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights
The vitamin B6-responsive disorders (B6RDs) are a clinically and genetically heterogeneous group of rare, autosomal recessive conditions (Clayton, 2006) with the hallmark feature of seizures uniquely responsive to treatment by the B6 vitamers pyridoxine and/or pyridoxal-5′-phosphate (PLP) (Baumgartner-Sigl et al., 2007; Basura et al., 2009). PLP is a cofactor for over 160 distinct catalytic functions (Percudani and Peracchi, 2009), including enzymes involved in glucose, lipid and amino acid metabolism (John, 1995; Percudani and Peracchi, 2003; Eliot and Kirsch, 2004), and for the synthesis of neurotransmitters, making it an essential vitamer for normal brain function (Surtees et al., 2006).
Pyridoxine-dependent epilepsy in zebrafish caused by Aldh7a1 deficiency
PYROXIDINE-DEPENDENT epilepsy (PDE, MIM #266100) is a rare autosomal recessively inherited metabolic disease (Gospe 2017) in which intractable and recurrent neonatal or infantile seizures are alleviated uniquely by high doses of pyridoxine (Pyr, vitamin B6) or pyridoxal 5′-phosphate (PLP) (Baxter 2001; Mills et al. 2006; Stockler et al. 2011). When untreated, PDE can lead to death, usually of status epilepticus (Gospe 2017). This condition is caused by mutations in the lysine degradation gene ALDH7A1 (Mills et al. 2006) that encodes α-aminoadipic-semialdehyde-dehydrogenase, which is also known as “Antiquitin” (Lee et al. 1994) due to its remarkable level of conservation through evolution (Supplemental Material, Figure S1). Loss of ALDH7A1 enzyme function leads to the pathogenic accumulation of the lysine intermediates aminoadipate semialdehyde (AASA) and its cyclic equilibrium form piperideine 6-carboxylate (P6C) in tissues including the central nervous system (CNS)  (Figure 1). P6C has been shown to react with and inactivate PLP (the active form of vitamin B6), a cofactor for over 140 enzymes including those involved in neurotransmission (Percudani and Peracchi 2003). It is thus hypothesized that the local or global depletion of PLP results in the Pyr-dependent seizures (Clayton 2006), possibly via disturbance of the PLP-dependent biosynthesis of γ-aminobutyric acid (GABA), the main cerebral inhibitory neurotransmitter. So far, clinical data from cerebrospinal fluid (CSF) measurements of these compounds were inconclusive and the pathophysiology of PDE remains to be fully elucidated.