Anu Suomalainen Wartiovaara - Selected Publications#

1. Mito T., Vincent AE, Faitg J, Taylor R, Khan NA, McWilliams TG, Suomalainen A. Mosaic dysfunction of mitophagy in mitochondrial muscle disease. In press, Cell Metabolism. IF 27.29

This paper is the first evidence in a mammalian disease that mitophagy (organellar autophagy targeting mitochondria) contributes to disease. Our evidence shows that stress responses, such as mitophagy may be induced in adjacent cells even in opposite manner, indicating that disease-relevant treatment development has to consider possible mosaic expression of disease, when choosing an intervention.

2. Pirinen E, Auranen M, Khan NA, Brilhante V, Urho N, Pessia A, Hakkarainen A, Kuula J, Heinonen U, Schmidt MS, Haimilahti K, Piirilä P, Lundbom N, Taskinen MR, Brenner C, Velagapudi V, Pietiläinen KH, Suomalainen A. Niacin cures systemic NAD+ defiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell Metab 2020; 31: 1078–1090. IF 27.29

The first report of NAD+-deficiency in a human metabolic disease, and a pilot trial of NAD+boosters to treat mitochondrial myopathy patients, to follow up our promising preclinical mouse study (EMBO Mol Med 2014). The first NAD-based therapy with beneficial effects for mitochondrial disease patients and the first indication that muscle NAD+ deficiency is reflected in the blood (basis of our methodological patent application & NADmed.fi project). International patient studies ongoing.

3. Forsström S, Jackson CB, Carroll CJ, Kuronen M, Pirinen E, Pradhan S, Marmyleva A, Auranen M, Kleine I-M, Khan NA, Roivainen A, Marjamäki P, Liljenbäck H, Wang L, Battersby BJ, Richter U, Velagapudi V, Nikkanen J, Euro L, Suomalainen A. Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions. Cell Metab 2019; 30: 1040–1054.

IF 27.29 The first report of stage-wise progression of mammalian mitochondrial stress response. We show that already before disease manifestation, a restorative metabolic response occurs, involving metabokines FGF21 and GDF15. When the disease signal is extended, a second response stage is initiated in muscle, FGF21 is secreted to circulation, and the disease manifests. We show major systemic effects on metabolism, including a response from muscle to brain via FGF21.

4. Ignatenko O, Chilov D, Paetau I, Vashchinkina E, Jackson C, Capin G, Paetau A, Terzioglu M, Euro L, Suomalainen A. Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy. Nature Commun 2018; 9: 70. IF 14.92

We show here that astrocytes and neurons in the brain respond highly differently to similar stress (postnatal mtDNA depletion). We show that astrocytes show remarkable pathologic reactivation upon mtDNA stress, resulting in progressive spongiotic encephalopathy, a typical manifestation of mitochondrial disease in children. Neuronal mtDNA stress causes late-onset, acute neuronal death. Our study shifts the spotlight from neurons to astrocytes in mitochondrial brain pathology, a previously unexplored field, and presents the first mouse model for spongiotic mitochondrial brain diseases.

5. Khan NA, Nikkanen J, Yatsuga S, Jackson C, Wang L, Pradhan S, Kivelä R, Pessia A, Velagapudi V, Suomalainen A. mTORC1 regulates integrated mitochondrial stress response and mitochondrial myopathy progression. Cell Metab 2017; 26: 419–428. IF 27.29

This is a mechanistic follow-up to Nikkanen et al. paper 2016, and the first report of mTORC1 involvement in mitochondrial disease and stress responses. We report that rapamycin is able not only to stop progression of the disease, but actually reverse it, providinginteresting preclinical data for patient studies, ongoing elsewhere.

6. Nikkanen J, Forsström J, Euro L, Paetau I, Kohnz RA, Wang L, Chilov D, Viinamäki J, Roivainen A, Marjamäki P, Liljenbäck H, Ahola S, Buzkova J, Terzioglu M, Khan NA, Pirnes-Karhu S, Paetau A, Lönnqvist T, Sajantila A, Isohanni P, Tyynismaa H, Nomura DK, Battersby B, Velagapudi V, Carroll CJ, Suomalainen A. Mitochondrial DNA replication defects disturb cellular dNTP pools and remodel one-carbon metabolism. Cell Metab 2016; 23: 635–648. IF 27.29

Discovery of major remodeling of whole-cellular anabolic growth pathways as a stress-response to primary mitochondrial dysfunction, with high relevance for tissue-specific manifestations, stress responses and therapy targets. Widely confirmed in independent international follow-up studies.

7. Hämäläinen RH, Landoni JC, Ahlqvist KJ, Goffart S, Ryytty S, Rahman MO, Brilhante V, Icay K, Hautaniemi S, Wang L, Laiho M, Suomalainen A. Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias. Nature Metab 2019; 1: 958–965. IF 7.74 The report addresses an important conundrum in the field: how mtDNA mutagenesis contributes to aging-like symptoms. Our previous data (Cell Metab 2012; Cell Rep 2015; Nat Comm 2015) directed our interest to somatic stem cells. We show here that increased mitochondrial DNA replication steals nucleotides from the nucleus, stalling genomic DNA replication, and causing nuclear genomic DNA breaks in stem cells. These findings present a unifying explanation of mitochondrial and nuclear progeria models and place mitochondria to an important role in whole-cellular dNTP pool regulation in stem cells. (Featured as previews in Nature Rev Mol Cell Biol and in Nature Metabolism)

8. Vasilescu C, Ojala TH, Brilhante V, Ojanen S, Hingerding H, Palin E, Alastalo TP, Koskenvuo J, Hiippala A, Jokinen E, Jahnukainen T, Lohi J, Pihkala J, Tyni TA, Carroll CH, Suomalainen A. Genetic basis of severe childhood-onset cardiomyopathies. J Am Coll Cardiol 2018; 72: 2324–2338. IF 24.09

We present the first country-wide cohort study with clinical and genetic characterization of 66 children with severe childhood-onset CMP. We report a DNA diagnosis for 40% of patients, with novel genes and novel phenotypes for known CMP genes. Importantly, our study gives phenotype-genotype tools for prognostic evaluation and prioritization of cardiac transplants for always progressing vs spontaneously stabilizing defects, all initially life-threatening. We show that most DNA defects in childhood CMPs are de novo, emphasizing the need of NGS diagnostics. (Featured in editorial in JACC).

9. Nikkanen J, Landoni JC, Balboa D, Haugas M, Partanen J, Paetau A, Isohanni P, Brilhante V, Suomalainen A. A complex genomic locus drives mtDNA replicase POLG expression to its disease-related nervous system regions. EMBO Mol Med 2018; 10: 13–21. IF 10.29

We report that DNA polymerase gamma, the mitochondrial DNA replicase, is encoded by an unusually complex genomic locus in nuclear choromosome 15, involving expression driven by CNS-specific enhancer-elements and regulatory RNAs with local and distal effects.

10. Suomalainen A, Battersby BJ. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol 2017; 19: 77-92. IF 94.44 Invited review.