Diabetes Metab J.  2021 Nov;45(6):853-865. 10.4093/dmj.2021.0138.

Mitochondrial TFAM as a Signaling Regulator between Cellular Organelles: A Perspective on Metabolic Diseases

• Koh JH
• Kim YW
• Seo DY
• Sohn TS

• KMID: 2522724
• DOI: http://doi.org/10.4093/dmj.2021.0138

Abstract

Tissues actively involved in energy metabolism are more likely to face metabolic challenges from bioenergetic substrates and are susceptible to mitochondrial dysfunction, leading to metabolic diseases. The mitochondria receive signals regarding the metabolic states in cells and transmit them to the nucleus or endoplasmic reticulum (ER) using calcium (Ca²⁺) for appropriate responses. Overflux of Ca²⁺ in the mitochondria or dysregulation of the signaling to the nucleus and ER could increase the incidence of metabolic diseases including insulin resistance and type 2 diabetes mellitus. Mitochondrial transcription factor A (Tfam) may regulate Ca²⁺ flux via changing the mitochondrial membrane potential and signals to other organelles such as the nucleus and ER. Since Tfam is involved in metabolic function in the mitochondria, here, we discuss the contribution of Tfam in coordinating mitochondria-ER activities for Ca²⁺ flux and describe the mechanisms by which Tfam affects mitochondrial Ca²⁺ flux in response to metabolic challenges.

Keyword

Calcium; Cell nucleus; Diabetes mellitus, type 2; Endoplasmic reticulum; Mitochondria; TFAM protein

Figure

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  Fig. 1. Schematic illustration of the mechanism underlying the mitochondrial membrane potential (ΔΨm) and electron transport chain (ETC) as well as a summary of subunits of the four-ETCs and adenosine triphosphate (ATP) synthase (complex V) encoded by nuclear and mitochondrial genes. The five complexes are embedded in the inner mitochondrial membrane. ΔΨm is generated via a proton pump comprising complex I, III, and IV, and the electron is sequentially transferred from complex I to IV, referred to as the ETC. The proton pump-induced proton gradient between the intermembrane space and matrix generates ΔΨm. The flow of protons through ATP synthase from the intermembrane space to the matrix is coupled with ATP synthesis. Indicated below each complex is the number of protein subunits encoded by nuclear (nDNA) and mitochondrial genomes (mtDNA). OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; NAD(H), nicotinamide adenine dinucleotide; CoQ, coenzyme Q; FAD(H), flavin adenine dinucleotide; Cyt C, cytochrome C; ADP, adenosine diphosphate .

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  Fig. 2. Mitochondria contacts endoplasmic reticulum (ER) and regulates cellular calcium (Ca2+) flux. Na+/Ca2+ exchanger (NCLX) regulates Ca2+ efflux from the mitochondria to the cytosol. The sarco/endoplasmic reticulum Ca2+ ATPase (Serca) in the ER membrane can take up Ca2+ into the ER lumen. Inositol triphosphate (IP3) binds to its own receptor (IP3R) leading to ER Ca2+ efflux in the cytosol or the mitochondria via a voltage-dependent anion channel (VDAC) at the outer mitochondrial membrane (OMM); in turn, the mitochondrial calcium uniporter (MCU) transfers it across the inner mitochondrial membrane (IMM). Ca2+ is necessary for the activation of pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (IDH), and α-ketoglutarate (KGDH); thus, Ca2+ flux in the mitochondria is a key process for the tricarboxylic acid (TCA) cycle to provide nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH) for the electron transport chain (ETC). Mitofusin (MFN) induces mitochondria-ER physical tethering to provide a stable association.

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  Fig. 3. A schematic illustration of the hypothesized role of mitochondrial transcription factor A (Tfam). Mechanism by which Tfam sends calcium (Ca2+) signals to the nucleus. Na+/Ca2+ exchanger (NCLX) and mitochondrial calcium uniporter (MCU) are embedded at the inner mitochondrial membrane (IMM). The activity of these channels can be affected by ΔΨm flux, which can be regulated by Tfam. Thus, Tfam-driven ΔΨm can transmit Ca2+ signals via NCLX/voltage-dependent anion channel (VDAC) to the nucleus. Tfam can regulate the transcription of NCLX and sarco/endoplasmic reticulum Ca2+ ATPase (Serca); however, the specific mechanism is not clear in metabolic cells. Tfam increases calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), 5’ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1), and peroxisome proliferator-activated receptor delta (PPARδ). The Tfam-induced increase in these proteins seems to be regulated by Ca2+ signaling. ER, endoplasmic reticulum.

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  Fig. 4. A schematic illustration of the summary of the dysregulation of mitochondrial calcium (Ca2+) flux in type 2 diabetes mellitus (T2DM). Lower mitochondrial transcription factor A (Tfam) levels in T2DM may serially induce mitochondrial Ca2+ dysregulation through ΔΨm/Ca2+ channels. (1) Lower Tfam levels in mitochondria clearly reduce the mitochondrial complex that regulates proton pumps, (2) leading to dysregulation of ΔΨm that controls the Na+/Ca2+ exchanger (NCLX) channel. (3) Overload of Ca2+ induced by NCLX decreases tricarboxylic acid (TCA) cycle activity, resulting in reduced supply of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH) for the electron transport chain (ETC) proton pump; especially, overloaded Ca2+ increases inner mitochondrial membrane (IMM) depolarization and decreases ΔΨm for NCLX activity. Overloaded Ca2+ in (3) matrix and (4) intermembrane space may trigger apoptosis. (5) Dysregulation of Ca2+ by inositol triphosphate receptor (IP3R) and sarco/endoplasmic reticulum Ca2+ ATPase (Serca) is clearly linked to mitochondrial dysfunction and metabolic disease. (6) Loss of mitofusin (MFN) downregulates stable contact of the mitochondria and endoplasmic reticulum (ER), leading to T2DM. (7) Overloaded Ca2+ in cytosol also increases the incidence of T2DM. (8) Loss of Ca2+ signaling into the nucleus from the mitochondria may inhibit the transcription of NCLX, Serca, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and peroxisome proliferator-activated receptor delta (PPARδ), (9) glucose transporter type 4 (GLUT4) expression is regulated by PPARδ. This can be a caused by a metabolic disease. MCU, mitochondrial calcium uniporter; VDAC, voltage-dependent anion channel.

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