Mitochondrial morphology regulates organellar Ca2+ uptake and changes cellular Ca2+ homeostasis

Author(s):Show less -

Kowaltowski, Alicia J. ^[1] ; Menezes-Filho, Sergio L. ^[1] ; Assali, Essam A. ^{[2, 3]} ; Goncalves, Isabela G. ^[1] ; Cabral-Costa, Joao Victor ^[1] ; Abreu, Phablo ^[1] ; Miller, Nathanael ^{[2, 3]} ; Nolasco, Patricia ^[4] ; Laurindo, Francisco R. M. ^[4] ; Bruni-Cardoso, Alexandre ^[1] ; Shirihai, Orian S. ^{[2, 3]}

Affiliation

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil

^[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 - USA

^[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol, Los Angeles, CA 90095 - USA

^[4] Univ Sao Paulo, Fac Med, Inst Coracao InCor, Hosp Clin, Lab Biol Vasc, Biol Cardiovasc Translac LIM 64, Sao Paulo - Brazil

• Document type: Journal article
• Source: FASEB JOURNAL; v. 33, n. 12, p. 13176-13188, DEC 2019.
• Web of Science Citations: 0

Abstract

Changes in mitochondrial size and shape have been implicated in several physiologic processes, but their role in mitochondrial Ca2+ uptake regulation and overall cellular Ca2+ homeostasis is largely unknown. Here we show that modulating mitochondrial dynamics toward increased fusion through expression of a dominant negative (DN) form of the fission protein {[}dynamin-related protein 1 (DRP1)1 markedly increased both mitochondrial Ca2+ retention capacity and Ca2+ uptake rates in permeabilized C2C12 cells. Similar results were seen using the pharmacological fusion-promoting M1 molecule. Conversely, promoting a fission phenotype through the knockdown of the fusion protein mitofusin (MFN)-2 strongly reduced the mitochondrial Ca2+ (u)ptake speed and capacity in these cells. These changes were not dependent on modifications in mitochondrial calcium uniporter expression, inner membrane potentials, or the mitochondrial permeability transition. Implications of mitochondrial morphology modulation on cellular calcium homeostasis were measured in intact cells; mitochondrial fission promoted lower basal cellular calcium levels and lower endoplasmic reticulum (ER) calcium stores, as indicated by depletion with thapsigargin. Indeed, mitochondrial fission was associated with ER stress. Additionally, the calcium-replenishing process of store-operated calcium entry was impaired in MFN2 knockdown cells, whereas DRP1-DN promoted fusion resulted in faster cytosolic Ca2+ increase rates. Overall, our results show a novel role for mitochondrial morphology in the regulation of mitochondrial Ca2+ uptake, which impacts cellular Ca2+ homeostasis. (AU)

• FAPESP's process: 16/18633-8 - Expansion of satellite cell pools in adult skeletal muscle: role of bioenergetics and mitochondrial alterations induced by aerobic exercise
• Grantee: Phablo Sávio Abreu Teixeira
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 14/24511-7 - Mechanisms and implications of the mTORC1 signaling pathway in the cardiovascular phenotype of Marfan Syndrome
• Grantee: Patricia Nolasco Santos
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/14713-0 - Mitochondrial Ca2+ Handling in the Central Nervous System and Energy Metabolism Regulation
• Grantee: João Victor Cabral Costa
• Support type: Scholarships in Brazil - Doctorate